JP2019512519A - Pd (II) -Catalyzed Enantioselective .BETA.-Methylene C (sp3) -H Bond Activation - Google Patents

Abstract

Chiral Acetyl-Protected Aminoethyl Capable of Pd (II) -Catalyzed Enantioselective Arylation or Heteroarylation of Ubiquitous Prochiral .BETA.-Methylene CH Bonds of Aliphatic Amides Providing Alternative Cleavage to Build .BETA.-Chiral Centers Disclosed are quinoline (APAQ), pyridine and imidazoline ligands. Systematic formation of the ligand structure, instead of 5-membered chelation of these types of ligands with Pd (II), 6-membered chelation accelerates C (sp3) -H activation, thereby It is revealed that it is important to achieve the enantioselectivity of quinoline and pyridine ligands. 【Selection chart】 None

Description

Description Government Support This invention was made with government support under NIGMS 2 R01 GM084019 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.

  The present invention relates to a process for the preparation of β-arylated and β-heteroarylated carboxylic acid derivatives, more particularly aryl or hetero with high yield and high diastereoselectivity on the β-carbon of protected carboxylic acid substrates The present invention relates to Pd (II) catalyzed insertion of aryl substituents.

Enantioselective functionalization of prochiral CH bonds can lead to a wide variety of asymmetric reactions to prepare chiral compounds. Despite a great deal of effort, the scope and efficiency of enantioselective C (sp ³ ) -H activation reactions are by no means sufficient for the widespread use of asymmetric synthesis [Giri et al., Chem. Soc. Rev. .38, 3242-3272 (2009)]. Enantioselective carbene and nitrene insertions into C (sp ³ ) -H bonds have been demonstrated in both diastereoselective and enantioselective manner [Doyle et al., Chem. Rev. 110, 704- 724 (2010); Reddy et al., Org. Lett. 8, 5013-5016 (2006); Liang et al., Angew. Chem. Int. Ed. 45, 4641-4644 (2006); Zalatan et al., J. Am. Chem. Soc. 130, 9220-9221 (2008); and Milczek et al., Angew. Chem. Int. Ed. 47, 6825-6828 (2008)].
However, asymmetric C (sp ³ ) -H activation reactions due to metal insertion are largely limited to the asymmetry of CH bonds located at two different carbon centers. For example, asymmetrization of cyclopropyl and cyclobutyl CH bonds has been achieved with Pd (II) catalysts and chiral monoprotected amino acid ligands [Shi et al., Angew. Chem. Int. Ed. 47, 4882-4886 (2008) Wasa et al., J. Am. Chem. Soc. 133, 19598-19601 (2011); Xiao et al., J. Am. Chem. Soc. 136, 8138-8142 (2014); and Chan et al. J. Am. Chem. Soc. 137, 2042-2046 (2015)]. Asymmetry of the prochiral CH bond was also achieved by Pd (0) catalyzed intramolecular arylation as demonstrated in a series of pioneering studies [Nakanishi et al., Angew. Chem. Int. Ed. 50, 7438 -7441 (2011); Anas et al., Chem. Comm. 47, 11483-11485 (2011); Martin et al., Chem. Eur. J. 18, 4480-4484 (2012); and Saget et al., Angew. Chem. Int. Ed. 51, 2238-2242 (2012)] (Scheme 1 below).

In Scheme 1 and in Schemes 2 and 3 below, DG = directed group; PG = protecting group; OTf = trifluoromethanesulfonate; Ar = aryl group; Ac = acyl group; Et = ethyl group; and butyl group.
However, efficient chiral metal catalysts that allow enantioselective insertion into ubiquitous methylene CH bonds present on the same carbon center have not been developed so far. Attempts to achieve this process using a bidentate 8-aminoquinoline directing group and a chiral phosphoric acid amide have varied in enantiomeric ratio (er) (range 74:26 to 91: 9), alkyl CH for benzyl CH bond Binding gave lower er (63: 37) [Yan et al., Org. Lett. 17, 2458-2461 (2015)]. Recently, it has also been found that transient chiral directing groups perform enantioselective CH arylation of benzyl CH bonds [Zhang et al., Science 351, 252-256 (2016)].

  The solution to achieve regioselectivity at each CH bond in a given molecule remains elusive, but the choice of a single CH bond due to a specific distal relationship to existing functional groups at strategically important sites Activation could lead to broadly useful synthetic cleavage. When considering reverse synthetic cleavage for the asymmetric synthesis of .beta.-functionalized chiral carboxylic acids or amides, .alpha.,. beta.-isomers can be used as basic units which can be converted forward to the desired product using state-of-the-art conjugate addition reactions. Saturated esters or amides are immediately considered. Remarkably, Rh (I) -catalyzed asymmetric conjugate addition of α, β-unsaturated ketones with arylboronic acids provided an elegant method for preparing chiral β-arylated compounds [Berthon et al., “ Rhodium- and Palladium-Catalyzed Asymmetric Conjugate Additions "In Catalytic Asymmetric Conjugate Reactions A. Cordova, Eds. (Wiley, 2010), pp. 1-67; and Paquin et al., J. Am. Chem. Soc. 127, 10850 -10851 (2005)]. Thus, it was postulated that enantioselective arylation of methylene CH bonds by Pd (II) insertion at the beta position of the amide could provide an alternative cleavage to these very useful synthetic elements starting from saturated fatty acids (see below) Scheme 2).

In an earlier attempt, the inventors and co-workers adopted a chiral auxiliary approach to gain insights into stereoselective Pd insertion into the β-C (sp ³ ) -H bond [Giri et al., Angew. Chem. Int. Ed. 44, 2112-2115 (2005)]. However, the development of enantioselective versions of these diastereoselective β-CH iodination and acetoxylation reactions has not been successful because there is no suitable ligand compatible with the strongly coordinating oxazoline directing group [ Engle et al., J. Org. Chem. 78, 8927-8955 (2013)]. Utilizing a weakly coordinating amide-directed group in combination with a chiral monoprotected amino acid ligand (MPAA) led to the asymmetry (Scheme 1) of methyl, cyclopropyl and cyclobutyl CH bonds at two different carbon centers [Wasa] et al., J. Am. Chem. Soc. 133, 19598-19601 (2011); and Xiao et al., J. Am. Chem. Soc. 136, 8138-8142 (2014)]. Unfortunately, the MPAA ligand proved ineffective at promoting palladium insertion into the β-methylene CH bond.

In another embodiment, it is understood that nature constructs innumerable natural products through enantioselective β-CH hydroxylation of isobutyric acid [Goodhue et al., Biotechnol. Bioeng. 13, 203-214 (1971) Hasegawa et al., J. Ferment. Technol. 59, 203-208 (1981)]; furthermore, this process is adapted to the industrial preparation of Roche esters and as a valuable source of α-centric chirality for complex molecule synthesis Useful [Bode et al., Angew. Chem. Int. Ed. 40, 2082-2085 (2001); Paterson et al., Angew. Chem. Int. Ed. 43, 4629-4633 (2004); Lawhorn et al. Chem. Soc. 128, 16720-16732 (2006); Feng et al., J. Am. Chem. Soc. 138, 5467-5478 (2016)].
Starting from the central role of α-chiral centers in bulk preparation and reverse synthesis analysis of Roche esters [Corey et al. Eds., Enantioselective Chemical Synthesis: Methods, Logic and Practice (Direct Book Publishing, Dallas, TX, 2010 ], Inventors and co-workers have long sought to develop a methodology to asymmetrize the isopropyl group of isobutyric acid derivatives by transition metal catalyzed CH functionalization and then expand the existing chiral pool.
Enantioselective β-methylene CH arylation has recently been realized [Chen et al., Science 353, 1023-1027 (2016)], which will be described later in this application, but asymmetry of the isopropyl group is basically It is a different task. This task is reflected by analysis of the steric environment associated with each CH insertion intermediate.
While CH activation of methylene requires steric differentiation between bulky alkyl groups and methylene CH bonds, asymmetrization of the isopropyl moiety is relatively small α with the α-hydrogen atom of the isopropyl group Differentiation from methyl groups is required. This latter differentiation with a transition metal catalyst has a small difference in size between (A) methyl groups and αC-H bonds, and (B) prochiral centers (α carbons) are methylene when it is attempted to asymmetricize isopropyl groups. As with CH activation, it is difficult because it does not interact directly with the linked transition metal catalyst. As a result, the resulting chiral centers are further separated from the chiral centers of the catalyst, making chiral recognition significantly more difficult.

  To date, intermolecular asymmetrization of the isopropyl group was only possible with substrates containing large α-substituents to help amplify the chiral recognition in the transition state [Giri et al., Angew. Chem. Int. Ed. 44. Giri et al., Angew. Chem. Int. Ed. 44, 7420-7424 (2005); Xiao et al., J. Am. Chem. Soc. 136, 8138-8142 (2014). He et al., Angew. Chem. Int. Ed. 54, 15840-15844 (2015)]. Related work on asymmetrization of α-dialkyl groups by CH activation in other laboratories is limited to intramolecular Pd (0) -catalyzed CH arylation [Nakanishi et al., Angew. Chem. Int. Ed. 50] Chem. Comm. (Camb.) 47, 11483-11485 (2011); Martin et al., Chem. Eur. J. 18, 4480-4484 (2012); Saget et al., Angew. Chem. Int. Ed. 51, 2238-2242 (2012); Larionov et al., Chem. Sci. 4, 1995-2005 (2013); Holstein et al., ACS Catal. 4300-4308 (2015); Murai et al., J. Org. Chem. 80, 5407-5414 (2015); Yang et al., Chem. Sci. Advance article, DOI: 10.1039 / C6SC04006C; Holstein et al., Angew. Chem. Int. Ed. 55, 2805-2809 (2016)].

Formal enantioselective intermolecular .beta.-arylation of inspiring isobutyrate was demonstrated with moderate enantioselectivity (67: 33-77: 23 er) [Renaudat et al., Angew. Chem. Int. Ed. 49, 7261-7265 (2010)]. In this reaction, .alpha.-lithiation precedes the .alpha.-palladation reaction, after which .beta.-hydrido elimination gives the corresponding olefin intermediates. The subsequent double bond enantioselective carbopalladation reaction is responsible for the chiral induction rather than the chiral recognition of the geminal methyl group.
As described in detail below, chiral acetyl-protected aminoethyl quinoline (APAQ) ligands and similarly structured oxazolines and pyridines are prepared and used to achieve enantiomeric ratios (er) up to 96: 4 and 94% It enables Pd (II) catalyzed enantioselective arylation of β-methylene CH bonds of aliphatic amides in high yields (Scheme 3 below). A wide variety of simple aliphatic amides as well as aryl iodide coupling partners are compatible with this reaction.

Design of these novel chiral ligands integrate C (sp ³⁾ important structural motifs that previous quinoline and acetyl-protected amino acids ligands which are known to promote -H activation [Wasa et al J. Am. Chem. Soc. 134, 18570-18572 (2012); and Chan et al., Nat. Chem. 6, 146-150 (2014)]. Remarkably, the adoption of a 6-membered chelation of APAQ ligand and Pd (II) is important for the acceleration of C (sp ³ ) -H activation and hence the control of stereoselectivity. In contrast, acetyl protected aminomethyl quinoline, coordinated to Pd (II) by 5-membered chelation, is completely inactive in this reaction.

SUMMARY OF THE INVENTION Chiral ligand compounds (L) whose structure corresponds to Formula A below are contemplated. In the following formula A

R ³ is a C ₁ -C ₄ alkyl group or a fluoro-substituted benzoyl group; the depicted cyclic moiety (ring) in which R ⁵ and R ⁶ may be substituents is one ring or 5 or 6 atoms respectively R is a cyclic ring structure comprising two fused rings containing in the ring; Z is oxygen (O) or, when part of a double bond, CH; R ⁵ and R ⁶ are , Identical or different, and hydride, halogen other than iodo, linear, branched and cyclic C ₁ -C ₇ hydrocarbyl, C ₁ -C ₇ hydrocarbyloxy, carboxy C ₁ -C ₆ hydrocarbyl, trifluoromethyl, C ₁ -C ₆ hydrocarbyl Boyle, nitro, C ₁ -C ₆ hydrocarbylthio oxy, and cyano group, or a ring are independently selected from the group consisting of benzyl group substituted with 1 to 5 fluoro groups; R ⁷ represents a linear, branched or cyclic C ₁ -C ₇ hydrocarbyl radical, or a C ₁ -C ₇ hydrocarbylcarbonyl Be a aryloxy group; "n" is zero or 1, when n is zero Thus, there is no carbon atoms and R ⁷ itself with R ^7, depicted ring, R ³ C (O) HN group R ¹⁰ is a straight, branched or cyclic C ₁ -C ₇ hydrocarbyl group, or a C ₁ -C ₇ hydrocarbyloxy group, which is unsubstituted or R ^{When 10} is a cyclic C ₅ -C ₇ hydrocarbyl group (preferably phenyl or benzyl) or a C ₅ -C ₇ hydrocarbyloxy group, they are the same or different and linear, branched and cyclic C ₁ -C ₇ Hydrocarbyl groups, as well as one or two substituents R ⁸ and R ⁹ independently selected from the group consisting of C ₁ -C ₇ hydrocarbyloxy groups; and atoms with vicinal asterisks are chiral.
In some preferred embodiments where n is 1 and Z is CH, the structure of the compound of Formula A corresponds to Formula A1 or A2 below.

  In other embodiments in which n is 1 and Z is oxygen, the structure of the compound of formula A corresponds to the following formula A3, or when n is zero and Z is oxygen, the structure of the compound is It corresponds to the following formula A4.

Particular preference is given to the compounds of the formulas A-1 and A-4.
In a further additional independent preference, R ³ C (O) is preferably acetyl. R ⁷ is a linear C ₁ -C ₃ hydrocarbyl group or a C ₁ -C ₃ hydrocarbyloxy group. When ring R is quinolinyl or pyridinyl, R ¹⁰ is preferably a phenyl or benzyl group, and the ring structure may contain two substituents C ₁ -C ₅ hydrocarbyl groups, R ⁸ and R ⁹ , They are identical substituents and a) are attached to the 3 and 5 position of the ring or to the 2 and 6 position of the ring; R ⁸ and R ⁹ are both preferably t-butyl And R ⁷ and R ¹⁰ phenyl rings are in a syn or anti relationship.

Pd (II) catalyzed chiral insertion of aryl or heteroaryl substituents into the CH bond at the β-carbon of a protected prochiral carboxylic acid substrate, the enantiomer ratio (er) of which is such that one enantiomer is the other enantiomer Also contemplated are methods for providing larger insertion products (chiral products). The method comprises the following steps:
a) a dispersed or dissolved therein (i) a protected prochiral carboxylic acid substrate molecule of formula I, (ii) an excess of the formula I

Aromatic or heteroaromatic iodide reactant, (iii) catalytic amount of Pd (II) catalyst, (iv) amount of about 5 to about 20 mole percent based on the amount of protected carboxylic acid substrate molecule of Formula I A reaction mixture comprising a chiral acyl-protected ligand (L) of formula A (above), and (v) a solvent having an excess of an oxidized silver compound relative to the protected carboxylic acid substrate at about 70 ° C. Heating in a closed pressure vessel at a temperature of ~ 120 ° C. The reaction mixture is subjected to an insertion reaction such that its enantiomeric ratio (er) is maintained for a time and temperature sufficient to form an insertion product which is greater for one enantiomer than the other.

In the molecules of the formula I i) R ^a is hydrogen (H; hydride), a protected amino group (NPG) or a C ₁ -C ₆ hydrocarbyl linear or branched substituent, R ^b and R ^c One or two of are hydrides. An illustrative amino protecting group (NPG) is described below. R ^b and R ^c groups, when not hydrides, are C ₁ -C ₁₃ hydrocarbyl straight-chain or branched or cyclic aliphatic groups; or respectively nitrogen or two nitrogen and one oxygen It is a (methyl) C ₆ -C ₁₀ aromatic or heteroaromatic group containing up to 3 heteroatoms which may be obtained. Illustrative substituents include (methyl) phenyl (benzyl), 1- or 2- (methylnaphthyl), 3- (methyl) pyridinyl, 2- (methyl) purinyl and the like. The ring of (methyl) C ₆ -C ₁₀ aromatic or heteroaromatic group is unsubstituted or halogen (fluoro, chloro and bromo; ie other than iodo), C ₁ -C ₆ hydrocarbyl, C ₁ -C ₆ hydrocarbyloxy, carboxy C ₁ -C ₆ hydrocarbyl, trifluoromethyl, C ₁ -C ₆ hydrocarbyl Boyle, C ₁ -C ₆ hydrocarbyl carboxylate, nitro, C ₁ -C ₆ hydrocarbylthio oxy, is cyano and protected It is substituted with up to three substituents independently selected from one or more of the group consisting of amino.
X in the molecule of formula I is an NHR ² group and R ² is a perfluorinated p-tolyl group [4- (CF ₃ ) C ₆ F _4] ], OH, or an -OC ₁ -C ₁₂ hydrocarbyl group Thus, X is NH [4- (CF ₃ ) C ₆ F ₄ ], NOH or NH-OC ₁ -C ₁₂ , more preferably a NH-OC ₁ -C ₆ hydrocarbyl group.
Among the preferred protected carboxylic acid substrate molecules of Formula I are those in which R ^a and R ^b are both hydrides (hydrogen), such that the structure of the protected prochiral carboxylic acid substrate molecule of Formula I is It corresponds to the compound of the following formula Ia.

Wherein R ^c and X are as defined above.
In another embodiment, the structure of the protected prochiral carboxylic acid substrate molecule of Formula I corresponds to Formula Ib below, wherein X, R ^b and R ^c are as defined above, but R ^b and R ^c is preferably a C ₁ -C ₁₃ hydrocarbyl linear or branched or cyclic aliphatic group, more preferably the same C ₁ -C ₆ aliphatic group.

  In yet another embodiment, the structure of the protected prochiral carboxylic acid substrate molecule of Formula I corresponds to a compound of Formula Ic:

Wherein X, R ^b and R ^c are as defined above, and R ^b and R ^c are preferably identical C ₁ -C ₆ aliphatic groups.
The aromatic or heteroaromatic iodide reactant is not substituted other than the iodo group or contains up to three substituents in addition to the iodo group. Additional substituents include halogens other than iodo, C ₁ -C ₆ hydrocarbyl, C ₁ -C ₆ hydrocarbyloxy [—O-hydrocarbyl], trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ hydrocarboyl [— C (O) hydrocarbyl], C ₁ -C ₆ hydrocarbyl carboxylate [—C (O) O-hydrocarbyl], hydrocarbylthiooxy, nitro, cyano, methylenedioxy, C ₂ -C ₆ bicinyldioxyalkyl, eg 3,4- (α, β-ethylenedioxy) group (the following compound 2u) or 4,5- (γ, δ-hexylenedioxy), and C ₁ -C ₆ hydrocarbyl di-C ₁ -C ₆ alkyl It is independently selected from one or more of the group consisting of phosphonate groups.
The independent preferences described above for the ligands of Formula A are applicable to the use of the compounds in the contemplated method.
The insertion products produced thereby, which are larger in their enantiomer ratio (er) than in one enantiomer, the other enantiomer, can be recovered by standard organic chemistry means or be reacted further without recovery or purification Can. Recovery before further reaction is usually preferred.

The invention has several benefits and advantages.
One benefit is that in protected carboxylic acid substrate molecules, aromatic or heteroaromatic β-insertion products can be prepared at high enantiomeric ratios, with some insertion products having an enantiomeric ratio greater than 90 percent.
An advantage of the present invention is that the yield of intercalated product is also relatively high, with some products exceeding 80 percent.
Another benefit of the present invention is a chiral ligand that directs the stereospecificity of the insertion reaction.
Another advantage of the present invention is that it is possible to obtain high enantiomeric ratios of the insertion products of both enantiomers by appropriate choice of chiral ligands.
Yet another benefit of the present invention is that chiral ligands can often be recovered and reused.
Additional benefits and advantages will become apparent to those skilled in the art from the following description.

Definitions The following generally used organic chemistry abbreviations and symbols are sometimes used herein: as is well known, ^* = chiral atom; PG = protecting group; min = minute; h = hour; rt = room temperature; Ph = Phenyl, Ac = acetyl; Ms = methanesulfonyl; Ts = toluenesulfonyl; Tf = trifluoromethanesulfonyl; Me = methyl; MeO = methoxy; Ar _F = 2,3,5,6-tetrafluoro-4- (trifluoro Methyl); Ar _F NH ₂ = 2,3,5,6-tetrafluoro-4- (trifluoromethyl) aniline;

etc. As an abbreviation for further organic chemistry include the following: MeOH = methanol; EtOH = ethanol; ⁱ PrOH = isopropanol; THF = tetrahydrofuran; DME = dimethoxyethane; HMPA = hexamethylphosphoramide; Et ₃ N = Triethylamine HFIP = hexafluoro-2-propanol; Ac ₂ 0 = acetic anhydride; DCC = dicyclohexyl carbodiimide; TBAF = tetrabutylammonium fluoride; DEAD = diethyl azacarboxylate; EtOAc = ethyl acetate; DMAP = 4- (dimethylamino) pyridine Ac-Phe-OH = N-acetylphenylalanine; M-CPBA = metachloropropoxybenzoic acid; n-BuLi = n-butyllithium; Ac = acetyl; Bn = benzyl; Cbz = (benzyloxy) carbonyl; Boc = tert -Butyloxycarbonyl; Fmoc = fluorenylmethyloxycarbonyl; and TBS = tert-butyl-dimethy Silyloxy.

In the context of the present invention and the related claims, the following terms have the following meanings.
As used herein, the articles "a" and "an" are used to refer to one or more than one (ie, at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.
In this application the word "prochiral" is used to mean a molecule whose achiral center can be converted to a chiral center in a single step. Thus, an achiral molecule is considered to be a molecule having one or more chiral centers as well as an achiral center, which may be converted to additional chiral centers in one step.
The words "ortho", "meta" and "para" are used in their usual manner to refer to benzenoid compounds substituted "1-2", "1-3" and "1-4" respectively. When an iodo group is present in the aromatic or heteroaromatic reactant, the compound and numbering scheme are usually based on the iodo substituent at position 1 of the ring or ring system.

The word "hydrocarbyl" is used herein as an abbreviation for non-aromatic groups, and includes linear and branched aliphatic groups containing only carbon and hydrogen and alicyclic groups. Thus, alkyl, alkenyl and alkynyl groups are contemplated, while aromatic hydrocarbons such as phenyl and naphthyl are, strictly speaking, also hydrocarbyl groups, but as will be described later they are referred to as aryl groups in the present application.
When a particular aliphatic hydrocarbyl substituent is intended, the group is detailed as follows: C ₁ -C ₄ alkyl, methyl or hexenyl. Exemplary hydrocarbyl groups contain chains of 1 to about 7 carbon atoms, preferably 1 to about 4 carbon atoms.
Particularly preferred hydrocarbyl groups are alkyl groups. As a result, generalized and more preferred substituents can be elaborated by replacing the word "hydrocarbyl" with "alkyl" in any of the substituent groups listed in this application.
Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the like. Examples of suitable alkenyl groups include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like. . Examples of alkynyl groups include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl and the like.

When the word "hydrocarbyl" is used, the convention of removing the terminal "yl" and adding an appropriate suffix, because the resulting name may be similar to one or more substituents Follows the usual chemical suffix nomenclature except that it does not always follow. Thus, hydrocarbyl ethers are referred to as "hydrocarbyloxy" groups rather than "hydrocarboxy" groups, as they are likely to be more accurate when following the usual rules of chemical nomenclature. Illustrative hydrocarbyloxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclohexenyloxy groups and the like. On the other hand, hydrocarbyl groups containing —C (O) O-functionality are referred to as hydrocarboyl (acyl) groups because they are not ambiguous even with the use of the hydrocarbyl (acyl) suffix. Exemplary hydrocarboyl and hydrocarbyloxy groups include acyl and acyloxy groups, such as acetyl and acetoxy, acryloyl and acryloyloxy, respectively.
As those skilled in the art will appreciate, non-existent substituents such as C ₁ alkenyl groups are not intended to be encompassed by the word "hydrocarbyl" but such substituents having 2 or more carbon atoms are intended Ru.

A "carboxyl" substituent is a -C (O) OH group. C ₁ -C ₆ hydrocarbyl carboxylate is a C ₁ -C ₆ hydrocarbyl ester of the carboxyl group [—C (= O) —OC ₁ -C ₆ hydrocarbyl].
The term "aryl" alone or in combination refers to phenyl or naphthyl or other aromatic group. Aryl groups can be carbocyclic, containing only carbon atoms in the ring, or heterocyclic, such as the heteroaryl groups described below. A "heteroaryl" group is an aromatic heterocyclic ring substituent, preferably containing one, two, three or four atoms other than carbon in the ring. The heteroatom may be nitrogen, sulfur or oxygen. Heteroaryl groups may contain fused ring systems having a single five or six membered ring or two six or five membered rings and a six membered ring. Exemplary heteroaryl groups include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl and pyridazinyl: 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1,2,3- Triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl and isothiazolyl groups; 6 -Membered / 5-membered fused ring substituents, such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl and anthranilyl groups; and 6-membered / 6-membered fused rings, such as 1, 2 -, 1,4-, 2,3- and 2, 1-benzopyrrolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and 1,4-benzoxazinyl groups.
The term "halogen" means fluorine, chlorine or bromine. The term perfluorohydrocarbyl means hydrocarbyl groups in which each hydrogen is replaced by a fluorine atom. Examples of such perfluorohydrocarbyl groups are, in addition to the preferred trifluoromethyl, perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl.

The terms "amino protecting group" and "amine protecting group" as used herein refer to one or more selectively removable substituents generally utilized to block or protect the amino functionality on the amino group. Point to a group. Illustrative amine protecting groups are those used for solid phase peptide synthesis.
Examples of such amine protecting groups include formyl ("For"), trityl ("Trt"), phthalimido ("Phth"), trichloroacetyl, chloroacetyl, bromoacetyl, and iodoacetyl groups. . Urethane protecting groups such as t-butoxy-carbonyl ("Boc"), 2- (4-biphenylyl) propyl (2) oxycarbonyl ("Bpoc"), 2-phenylpropyl (2) oxycarbonyl ("Poc") , 2- (4-Xenyl) -isopropoxycarbonyl, 1,1-diphenyl-ethyl (l) oxycarbonyl, 1,1-diphenylpropyl (1) -oxycarbonyl, 2- (3,5-dimethoxyphenyl) propyl (2) oxycarbonyl ("Ddz"), 2- (p-5- toluyl) -propyl (2) oxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1 -Methylcyclohexanyl-oxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2- (4-tolylsulfonyl) ethoxycarbonyl, 2- (methyl-sulfonyl) -ethoxycarbonyl, 2- (triphenylphosphi) No) Ethoxycarbonyl, 9-Fluoroenylmethoxycarbonyl ("Fmoc"), 2- (Trimethyl-silyl) ethoxycarbonyl, allyloxycarbonyl, 1- (trimethyl-silylmethyl) prop-l-enyloxy carbonyl, 5-benziso Xalyl-methoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, 2-ethynyl (2) propoxycarbonyl, cyclopropylmethoxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl, Benzyloxycarbonyl ("Z"), 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxy-carbonyl, alpha-2,4,5-tetramethylbenzyloxycarbonyl ("Tmz"), 4-methoxybenzyloxycarbonyl , 4-fluorobenzyloxycarbonyl, 4-chlorobenzylo Xycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 4- (decyloxy) benzyloxycarbonyl and the like, benzoylmethylsulfonyl group, dithiasuccinoyl ("Dts") group, 2- (nitro) phenylsulfenyl group ("Nps"), 2- or 4-nitrophenylsulfonyl ( Amino protecting groups such as “Nos”) group, 4-toluenesulfonyl (“Ts”), diphenyl phosphine oxide group and the like.

The species of amine protecting group employed is usually not critical, as long as the derivatized amino group is stable to the conditions of the subsequent reaction and can be removed at an appropriate point without destroying the remainder of the compound. Preferred amine protecting groups are C ₁ -C ₅ acyl groups or phthaloyl groups.
Both the ligand and the reactant of formula I contain an amide group, the nitrogen atom of which is protected from reaction during the insertion reaction, but is optionally removable for later synthetic procedures. The ligand amide protecting group is preferably a C ₁ -C ₅ acyl group or a di, tri or pentafluorobenzoyl group. Amide nitrogen atom of the reactant compound, preferably perfluorinated p- tolyl group described above _{[4- (CF 3) C 6} F 4; or AR _F group], OH, or -OC ₁ -C ₁₂ hydrocarbyl group There, thus X is _{NH [4- (CF 3) C} 6 F 4], a NOH or NH-OC ₁ -C _12, is NH-AR _F and NH-OCH ₃ is the preferred X group.
Further examples of amino protecting groups encompassed by the above terms are well known in the organic synthesis and peptide arts and are described, for example, in the following documents: TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Sons, New York. NY, Chapter 7, 1991; M. Bodanzsky, Principles of Peptide Synthesis, 1st and 2nd revised ed., Sp ring er-Verlag, New York, NY, 1984 and 1993; and Stewart and Young, Solid Phase Peptide Synthesis, 2nd ed., Pierce Chemical Co, Rockford, IL 1984.

The related terms "protected amino" or "protected amine" define an amino group substituted with the above amino protecting group.
The terms "hydroxy protecting group" and "hydroxy protecting group" are easily cleavable groups which are attached to a hydroxyl group, such as tetrahydropyranyl, 2-methoxyprop-2-yl, 1-ethoxyeth-1-yl, methoxymethyl Methylthiomethyl, β-methoxyethoxymethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4 ', 4 "-trimethoxytrityl, benzyl, allyl, trimethylsilyl ("TMS"), t-butyldiphenylsilyl ("TBDPS"), (t-butyl) dimethylsilyl ("TBS" or "TBDMS"), triisopropylsilyl ("TIPS"), and 2,2,2- Trichloro-ethoxycarbonyl group etc. Ester groups such as C ₁ -C ₆ -hydrocarboyl esters such as acetate (“OAc”), propionate and hexanoate are also useful, as are benzyl ether (“Bn”) groups. Again, the species of the hydroxyl protecting group is such that the derivatized (protected) hydroxyl group is stable to the conditions of the subsequent reaction, and the protecting group can be removed at an appropriate point without destroying the rest of the compound As long as it is not usually important.
Further examples of hydroxy protecting groups are CB Reese and E Haslam, Protective Groups in Organic Chemistry, JGW McOmie Ed., Plenum Press, New York, NY, Chapters 3 and 4, 1973, and TW Greene and PGM Wuts, Protective Groups. in Organic Synthesis, 2nd ed., John Wiley and Sons, New York, NY, Chapters 2 and 3, 1991.

DETAILED DESCRIPTION The (i) prochiral protected substrate molecule I (described below), described below for the substituents, is dissolved or dispersed in a solvent at the use temperature and pressure according to the contemplated method.

(ii) excess aromatic or heteroaromatic iodide reactant, (iii) Pd (II) catalyst, (iv) chiral protecting ligand (L), for example a protected aminoethyl quinoline (APAQ) ligand This is provided), a reaction mixture containing protected aminoethylpyridine (APAP) or chiral monoprotected aminomethyl oxazoline (MPAO) etc., and (v) an oxidized silver compound. The reaction mixture is sealed in a suitable vessel and the contents heated to a temperature of about 80 to about 120 ° C. for a time sufficient for the reaction to proceed to the desired degree of arylation or formation of a heteroarylation product. The product can be recovered or maintained in the reacted reaction mixture and reacted further or recovered later.
After the reacted reaction mixture has cooled sufficiently for safety, a second amount of each identical or different iodide reactant, catalyst, ligand and silver oxidant are added and the vessel sealed, in this case Can be heated and maintained at elevated temperatures as before to give a second product containing two identical or different aryl or heteroaryl substituents. Typically, the second product is purified and recovered.

In the molecule of formula I: i) R ^a is hydrogen (H; hydride), a protected amino group (NPG), or a C ₁ -C ₆ hydrocarbyl linear or branched substituent, R ^b and R ^c One or two are hydrides. An illustrative amino protecting group (NPG) is described below. When not hydrides, the R ^b and R ^c groups may be C ₁ -C ₁₃ hydrocarbyl linear or branched or cyclic aliphatic groups; or each may be nitrogen or may be two nitrogens and one oxygen (Methyl) C ₆ -C ₁₀ aromatic or heteroaromatic groups containing up to 3 heteroatoms. Illustrative substituents include (methyl) phenyl (benzyl), 1- or 2- (methylnaphthyl), 3- (methyl) pyridinyl, 2- (methyl) purinyl and the like. The ring of (methyl) C ₆ -C ₁₀ aromatic or heteroaromatic group is unsubstituted or halogen (fluoro, chloro and bromo; ie other than iodo), C ₁ -C ₆ hydrocarbyl, C ₁ -C ₆ hydrocarbyloxy, carboxy C ₁ -C ₆ hydrocarbyl, trifluoromethyl, C ₁ -C ₆ hydrocarbyl Boyle, C ₁ -C ₆ hydrocarbyl carboxylate, nitro, C ₁ -C ₆ hydrocarbylthio oxy, is cyano and protected It is substituted with up to three substituents independently selected from one or more of the group consisting of amino.
In the molecule of formula I, X is an NHR ² group and R ² is a perfluorinated p-tolyl group [4- (CF ₃ ) C ₆ F _4] ], OH, or an -OC ₁ -C ₁₂ hydrocarbyl group Thus, X is NH [4- (CF ₃ ) C ₆ F ₄ ], NOH or NH-OC ₁ -C ₁₂ , more preferably an NH-OC ₁ -C ₆ hydrocarbyl group.
Among the preferred protected carboxylic acid substrate molecules of formula I, wherein R ^a and R ^b are both hydrido (hydrogen), and thus the structure of the protected prochiral carboxylic acid substrate molecule of formula I is a compound of formula Ia And the equivalent of

Wherein R ^c and X are as defined above.
In another embodiment, the structure of the protected prochiral carboxylic acid substrate molecule of Formula I corresponds to a compound of Formula Ib below, wherein X, R ^b and R ^c are as defined above but R is ^b and R ^c are preferably C ₁ -C ₁₃ hydrocarbyl linear or branched or cyclic aliphatic groups, more preferably identical C ₁ -C ₆ aliphatic groups.

  In yet another embodiment, the structure of the protected prochiral carboxylic acid substrate molecule of Formula I corresponds to a compound of Formula Ic:

Wherein X, R ^b and R ^c are as defined above, and R ^b and R ^c are preferably identical C ₁ -C ₆ aliphatic groups.
The aromatic or heteroaromatic iodide reactant is not substituted except for the iodo group or contains up to three substituents in addition to the iodo group. Additional substituents include halogens other than iodo, C ₁ -C ₆ hydrocarbyl, C ₁ -C ₆ hydrocarbyloxy [—O-hydrocarbyl], trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ hydrocarboyl [— C (O) hydrocarbyl], C ₁ -C ₆ hydrocarbyl carboxylate [—C (O) O-hydrocarbyl], hydrocarbylthiooxy, nitro, cyano, methylenedioxy, C ₂ -C ₆ bicinyldioxyalkyl, eg 3,4- (α, β-ethylenedioxy) group (the following compound 2u) or 4,5- (γ, δ-hexylenedioxy), and C ₁ -C ₆ hydrocarbyl di-C ₁ -C ₆ alkyl It is independently selected from one or more of the group consisting of phosphonate groups.
The independent preferences described above for the ligands of Formula A are applicable to the use of the compounds in the contemplated method.
The insertion products thereby produced, which have an enantiomer ratio (er) greater than that of the other for one enantiomer, can be recovered by standard organic chemistry means or be reacted further without recovery or purification it can. It is usually preferred to recover before further reaction.

In the substrate molecule of formula I
i) R and R ¹ may both be hydrogen (hydride), and at least one of R and R ¹ must be hydride. When not hydride, R or R ¹ groups are C ₁ -C ₁₂ hydrocarbyl linear or branched or cycloaliphatic groups; or C containing up to 3 heteroatoms which may be nitrogen, oxygen or sulfur respectively ₆ -C ₁₀ aromatic or heteroaromatic group. When not a hydride, the R or R ¹ group is unsubstituted or halogen (fluoro, chloro and bromo; ie other than iodo), C ₁ -C ₆ hydrocarbyl, C ₁ -C ₆ hydrocarbyloxy, carboxy C ₁ -C ₆ hydrocarbyl, one of the group consisting of trifluoromethyl, C ₁ -C ₆ hydrocarbyl Boyle, C ₁ -C ₆ hydrocarbyl carboxylate, nitro, C ₁ -C ₆ hydrocarbylthio oxy, cyano and protected amino Substituted with up to three substituents independently selected from the above; and
(ii) X is NHR ² group, R ² is usually abbreviated as Ar _F, the formula 4- (CF ₃₎ a perfluorinated p- tolyl group having C ₆ F _4, thus X is NH a _{[4- (CF 3) C 6} F 4]. When R ² is OH, the yield of the desired arylated or heteroarylated product is less than satisfactory. Good yields are obtained when R ² is a NH-OC ₁ -C ₁₂ hydrocarbyl group, in particular an NH-OC ₁ -C ₆ hydrocarbyl group such as a methyl or t-butyl group.

The substrate molecule of formula I is preferably present in the reaction mixture (pre-reaction) in about 0.05 to about 0.2 molar concentration, preferably about 0.1 to about 0.15 molar concentration.
Aromatic and heteroaromatic iodides are co-reactants in contemplated arylation or heteroarylation reactions. The iodide reactant is typically utilized in excess over the molar amount of a protected carboxylic acid substrate molecule (substrate) of Formula I.
Contemplated aromatic iodides (ArI) or heteroaromatic iodides (HetArI) are present in excess in the reaction mixture in excess of the amount of substrate of formula I. The excess is typically about 2 to about 4 equivalents per equivalent of substrate of Formula I, preferably about 2.5 to about 3 equivalents per equivalent of substrate of Formula I.
Contemplated aromatic or heteroaromatic iodides may be unsubstituted or substituted in addition to the iodo group, or may contain up to three substituents in addition to the iodo group. Contemplated substituents are halogen (fluoro, chloro and bromo), C ₁ -C ₆ hydrocarbyl, preferably C ₁ -C ₆ alkyl, C ₁ -C ₆ hydrocarbyloxy [—O-hydrocarbyl], preferably C ₁ -C ₆ alkoxy, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ hydrocarbyl Boyle [-C (O) hydrocarbyl, preferably C ₁ -C ₆ acyl, C ₁ -C ₆ hydrocarbyl carboxylate [-C (O) O-hydrocarbyl], hydrocarbylthiooxy, nitro, cyano, methylenedioxy, C ₂ -C ₆ bicynyldioxyalkyl, for example, 3,4- (α, β-ethylenedioxy) group (the following compound 2u Or independently selected from one or more of the group consisting of 4,5- (γ, δ-hexylenedioxy), and C ₁ -C ₆ hydrocarbyl di-C ₁ -C ₆ alkyl phosphonates.

Illustrative iodide substituted aryl rings are phenyl and naphthyl optionally substituted as described above. Illustrative iodide substituted heteroaryl ring compounds include aromatic monocyclic or bicyclic heterocycles containing one or more ring atoms other than carbon and optionally substituted as defined above .
A "heteroaryl" group preferably contains 1, 2, 3 or 4 (up to 4) ring atoms other than carbon (hetero atoms). The heteroatom may be nitrogen, sulfur or oxygen. Heteroaryl groups may contain fused ring systems having a single 5- or 6-membered ring or two 6-membered rings or two combinations of 5- and 6-membered rings. Exemplary heteroaryl groups include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1,2,3- Triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl and isothiazolyl groups; 6 -Membered / 5-membered fused ring substituents, such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl and anthranilyl groups; and 6-membered / 6-membered fused rings, such as 1, 2 -, 1,4-, 2,3- and 2,1-benzopyrrolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, C ₁ -C ₄ alkyl 4-oxo-4H-chromene carboxylates and 1,4-benzoxazinyl Le group is mentioned. When the iodide substituted heteroaryl group contains a ring -NH- group, the nitrogen atom is present as a C ₁ -C ₈ carboxamide, sulfonamide or substituted with a removable nitrogen protecting group as described above Is preferred.
Contemplated chiral ligands, L, may have the general structural formula A shown below.

In the ligand of formula A,
R ³ is a C ₁ -C ₄ alkyl group, preferably a C ₁ group, and consequently R ³ C (O) is an acetyl group or a fluoro-substituted benzoyl group, preferably at position 2 and 6 of the benzoyl ring Although containing two fluoro substituents in position, up to five fluoro substituents can be present on the benzoyl ring.
The depicted cyclic moiety (ring) in which R ⁵ and R ⁶ may be substituents is a cyclic ring structure containing one fused ring or two fused rings each containing 5 or 6 atoms in the ring, R ⁵ and R ⁶ are identical or different, hydride (H), halogen (fluoro, chloro and bromo; ie other than iodo), linear, branched and cyclic C ₁ -C ₇ hydrocarbyl such as phenyl and benzyl And the like, C ₁ -C ₇ hydrocarbyloxy, carboxy C ₁ -C ₆ hydrocarbyl, trifluoromethyl, C ₁ -C ₆ hydrocarboyl, nitro, C ₁ -C ₆ hydrocarbylthiooxy, and cyano or benzyl group The ring is independently selected from the group consisting of 1 to 5 fluoro groups).

The depicted cyclic moiety (ring) in which R ⁵ and R ⁶ may be substituents is a cyclic ring structure containing two fused rings each containing 5 or 6 atoms in one ring or ring. . The ring moiety may be aromatic but need not be. The ring member X is oxygen (O) or CH when part of a double bond.
R ⁷ is linear, branched and cyclic C ₁ -C ₇ hydrocarbyl, such as phenyl and benzyl and the like, or C ₁ -C ₇ hydrocarbyloxy.
"N" is zero or 1, when n is zero Thus, there is no carbon atoms and R ⁷ with R ^7, depicted ring, carbon atom carrying the R ³ C (O) HN group Directly attached to When Z is oxygen, n is preferably zero, and when Z is CH or CH ₂ , n is preferably one.
R ¹⁰ is a linear, branched or cyclic C ₁ -C ₇ hydrocarbyl group or a C ₁ -C ₇ hydrocarbyloxy group, which is unsubstituted or R ¹⁰ is a cyclic C ₅ -C ₇ hydrocarbyl group (Preferably phenyl or benzyl) or C ₅ -C ₇ hydrocarbyloxy groups, identical or different, and linear, branched and cyclic C ₁ -C ₇ hydrocarbyl groups, and C ₁ -C ₇ hydrocarbyloxy It is substituted by one or two substituents R ⁸ and R ⁹ which are independently selected from the group consisting of groups. In some embodiments, it is preferred that R ¹⁰ be a linear or branched C ₁ -C ₆ hydrocarbyl group.
Atoms with an adjacent asterisk are chiral.
Preferred ligands in which n is 1 and Z is CH, L are exemplified by compounds of the following formulas A-1 or A-2.

Preferably, R ⁵ and R ^{6 in} the ligand of A-1 or A-2 are hydrides.
In another embodiment, when n is 1 and Z is oxygen, the structure of the compound of formula A corresponds to the following formula A-3, or when n is zero and Z is oxygen: The structure of the compound corresponds to the following formula A-4.

Benzyl in which at least R ⁶ depicted as adjacent to the ring nitrogen in formulas A-3 and A-4 is preferably unsubstituted or substituted with a fluoro group at the 2 and 6 positions of the ring It is preferably a group. Particular preference is given to the compounds of the formulas A-1 and A-4.
The substituents R ^{5 to} R ¹⁰ , X and the asterisk in the compounds of each of formulas A1 to A4 are as defined above for the compounds of formula A.
In a further additional independent preference, R ³ C (O) is preferably acetyl. R ⁷ is a linear C ₁ -C ₃ hydrocarbyl group or a C ₁ -C ₃ hydrocarbyloxy group. When the ring R is quinolinyl or pyridinyl, R ¹⁰ is preferably a phenyl or benzyl group, which ring structure can contain two substituents C ₁ -C ₅ hydrocarbyl groups, R ⁸ and R ⁹ , They are identical substituents and are linked in a) in position 3 of the ring and 5 members or in b) in positions 2 and 6 of the ring; R ⁸ and R ⁹ are both preferably t-butyl; And R ⁷ and R ¹⁰ phenyl rings are in a relation of syn or anti.
The contemplated ligand L is used in the reaction in an amount of about 5 to about 20 mole percent. More preferably, ligand L is present in about 8 to about 17 mole percent based on the amount of substrate. The iodo group-containing reactant is typically present in excess over the amount of prochiral substrate. The excess is preferably about 2 to about 3 equivalents relative to 1 equivalent of prochiral substrate.

Useful Pd (II) catalysts are well known in the art. Exemplary catalysts include PdCl ₂ , Pd (TFA) ₂ , Pd (Piv) ₂ , [PdCl (C ₃ H ₅ )] ₂ , PdCl ₂ (PPh ₃ ) ₂ , Pd (PPh ₃ ) ₄ , Pd ₂ (dba _{) 3, [PdCl 2 (MeCN} ) 2], include _{[Pd (OTf) 2 · 4MeCN} ], and _{[Pd (BF 4) 2 ·} 4MeCN]. Among these catalysts, Pd (TFA) ₂ , Pd (Piv) ₂ and Pd (OAc) ₂ are currently preferred. Palladium acetate [Pd (OAc) ₂ ] is used as an example in the present application. The intended catalyst is utilized in catalytic amounts. The amount is typically about 5 to about 20 mole percent, more preferably about 10 to about 15 mole percent based on the moles of reaction substrate. The catalyst and ligand can be used in a relative ratio of catalyst to ligand of about 5: 1 to about 1: 5. More common amounts are from about 1: 2 to about 1: 1 catalyst to ligand. For quinoline ligands, the catalyst and ligand are typically utilized in approximately equal molar percentages, eg, within about 2 percent (± 2%) of each other as a percentage based on the moles of substrate.
A contemplated method utilizes an excess of about 1.5 to about 5 equivalents (mole) of oxidant, preferably about 2 to about 4 equivalents of oxidant per mole of reaction substrate. Although silver oxidant is typically used, oxygen and other mild oxidants can also be used. Illustrative catalysts include Ag (Piv), Ag (OAc), Ag ₂ O, AgTFA, AgOTf,

And Ag ₂ CO ₃ . Ag (OAc) is a preferred oxidant and is used as an example herein.
A contemplated reaction is carried out using components dissolved or dispersed in a solvent, with agitation that can be achieved on a laboratory scale by use of a magnetic stir bar. Additional agitation means such as shaking may also be utilized. Exemplary solvents include ^t BuCO ₂ Me, hexafluoroisopropanol (HFIP), ^t BuCN, ^t BuOMe, t-amyl OH, ^t Bu (C = O) Me, n-hexane, C ₆ F ₆ , toluene, dichloromethane DCM) and 1,2-dichloroethane (DCE). Of these materials, DCE, t-amyl OH and HFIP are preferred.
The contemplated method is preferably carried out under anhydrous conditions. Bench scale reactions using about 0.05 to about 0.10 millimoles of reaction substrate and appropriate amounts of other components are typically performed in about 0.5 to about 3 mL of solvent. From the ratio, it can be easily scaled up to larger quantities.
The electrophilic insertion is carried out at a temperature of about 30 ° C. to about 120 ° C., preferably at a temperature of about 35 ° C. to about 110 ° C., to form a reaction product, when the method of the present invention is carried out. Maintain for a sufficient time. More preferably, the temperature is about 60 ° C to about 100 ° C. The reaction time is typically about 15 to about 80 hours, usually about 18 to 50 hours.
The intended reaction is preferably carried out in a sealed reaction vessel, so the pressure at which the components are maintained is largely provided by the solvent used and there is some contribution from the reactants at the reaction temperature. Once the reaction is complete, the desired product can be recovered by conventional work-up procedures or can be left as is for further reaction as desired.

Results Using an electron-poor amide substrate 1 (described below), guided by the general goal of developing ligand-accelerated enantioselective CH activation of weakly coordinating substrates,

The effect of the chiral ligand was evaluated based on the extensively studied CH arylation reaction [Zaitsev et al., J. Am. Chem. Soc. 127, 13154-13155 (2005); Reddy et al. , Org. Lett. 8, 3391-3394 (2006); and Feng et al., Angew. Chem. Int. Ed. 49, 958-961 (2010)]. Following the previous finding that quinoline and pyridine ligands can accelerate C (sp ³ ) -H activation [He et al., Angew. Chem. Int. Ed. 55, 785-789 (2016)] (below table) A number of corresponding chiral ligands were prepared, including 1, L1-L3), L4, L5, and their activity under standard reaction conditions was investigated. The chiral carbon atom is indicated by an asterisk ( ^* ) adjacent to the chiral atom in the following structural formula.

^{* The} yield was determined by ¹ H NMR analysis of the crude product using CH ₂ Br ₂ as internal standard. The enantiomer ratio (er) was determined by chiral high performance liquid chromatography. The absolute configuration of L13, L21, L35 and L40b described later was determined by X-ray crystallography. HFIP = hexafluoro-2-propanol; Me = methyl group; Pr = propyl group; Bn = benzyl group; Ph = phenyl group.

Unfortunately, these monodentate chiral ligands do not significantly affect the stereochemistry of the Pd insertion step.
Quinoline coordination, considering the effectiveness of bidentate monoprotected amino acid ligand (MPAA) in controlling the stereochemistry of Pd-catalyzed asymmetrization of prochiral cyclopropyl and cyclobutyl CH bonds on two different carbon centers We developed bidentate ligands that incorporate structural motifs from both the molecule and the MPAA ligand. The critical role of the NHAc moiety of the MPAA ligand in the CH cleavage step revealed by experimental and computational studies [Cheng et al., J. Am. Chem. Soc. 136, 894-897 (2014)] Promoted the development of acetyl-protected aminomethyl quinoline ligands incorporating this coordinating moiety.
Unfortunately, the ligands L6-L8 resulted in a complete decrease in reactivity (NR). It was inferred that five-membered bidentate chelation with Pd (II) can lead to the formation of a stable but inactive palladium complex tetra-coordinated with two ligands. As such, they coordinate with Pd (II) through 6- and 7-membered chelate structures respectively (L9, L10), both significantly reduced compared to the corresponding 5-membered chelates (L9, L10, Table 1) Acetyl-protected aminoethyl quinoline (APAQ) and aminopropyl quinoline ligands were prepared which should have binding constants. Remarkably, such minor modifications restored reactivity with L9 and L10, thus providing novel bidentate ligand scaffolds for further development.

Aminopropyl quinoline L10 is more reactive than aminoethyl quinoline L9, but focused on the scaffold of aminoethyl quinoline L9 because of its ease of synthesis. A series of chiral acetyl protected aminoethyl quinoline ligands were prepared from 2-methyl quinoline and optionally pure sulfinyl imine using high efficiency asymmetric imine addition reaction of Ellman [Robak et al., Chem. Rev. 110, 3600-3740 (2010)].
First, the ligand L11 containing an α-methyl group at the chiral center was found to significantly enhance the reactivity despite giving insufficient enantioselectivity (er of 47:53) (75% yield). See Table 2. Next, when the α-methyl group was replaced with various alkyl groups, only the sterically bulky isopropyl group was found to give a significantly complete er reaching 27: 73, but the yield decreased ( L16).

  Further investigation of the alkyl substitution turned out to be less promising, but the results obtained with the α-phenyl substitution of L17 (76% yield, 29:71 er) are encouraging for ligand optimization Brought a clue. The various protecting groups for the amino group were investigated using L17 at hand (see Scheme 4 below). Replacing the methyl group in the acetyl protecting group with a more hindered alkyl or phenyl significantly reduced the yield. Other types of protecting groups such as carbamates and sulfonyls are completely inert.

^{* The} yield was determined by ¹ H NMR analysis of the crude product using CH ₂ Br ₂ as internal standard. The enantiomer ratio (er) was determined by chiral high performance liquid chromatography. NR does not react.

  Several APAQ ligands (L18-33) with various steric and electronic variations on the alpha-phenyl ring. Shown by the dramatically improved yield and enantioselectivity (85% yield, 19:81 er) obtained with ligand L32 with sterically hindered 3,5-di-tert-butylphenyl group It has been found that steric effects are predominant, as noted above. See Table 3 below.

At this optimization point, it was decided to introduce a second chiral center at the benzylic position to further improve the enantioselectivity. It is believed that the origin of stereoselectivity stems from the creation of less sterically hindered surfaces on square planar palladium complexes [Shi et al., Angew. Chem. Int. Ed. 47, 4882-4886 (2008); Wasa et al., J. Am. Chem. Soc. 133, 19598-19601 (2011); Xiao et al., J. Am. Chem. Soc. 136, 8138-8142 (2014); and Chan et al., J. Am. Chem. Soc. 137, 2042-2046 (2015)], Focus on variations of the syn-APAQ ligand with both substituents pointing up or down for chelation with Pd (II) I put it together.
Introducing a methyl group at the benzylic position (L34) resulted in a marked improvement in enantioselectivity (er at 90:10) while maintaining high yields. A slightly more bulky ethyl group (L35) further improved the enantioselectivity to an er of 92.5: 7.5. Further steric hindrance at the benzylic position reduced both yield and enantioselectivity (L 36-39). In order to gain insight into the stereochemical model of this unprecedented enantioselective palladium insertion process, the anti-APAQ ligands (L40a, L41) were also tested. See Table 4.

  Although the yield and enantioselectivity were significantly reduced with these two anti-ligands, the reversal of the chiral induction by changing the absolute configuration at the alpha position indicates that the chiral center adjacent to the amino group determines the enantioselectivity Suggest that (see Table 5).

^{* The} yield was determined by ¹ H NMR analysis of the crude product using CH ₂ Br ₂ as internal standard. The enantiomer ratio (er) was determined by chiral high performance liquid chromatography.
The reaction conditions were further optimized for the arylation of 2a using the optimal ligand L35 in hand to improve the enantioselectivity to an er of 95: 5 (see Table 6, entry 21).

^{* The} yield was determined by ¹ H NMR analysis of the crude product using CH ₂ Br ₂ as internal standard. The enantiomer ratio (er) was determined by chiral high performance liquid chromatography.

  The scope of aryl iodides was then investigated for this enantioselective β-C-H arylation (Table 7 below). Simple phenyl iodides and electron rich aryl iodides containing methyl and methoxy groups, except o-methoxyphenyl iodide (2 g, 89:11 er), gave excellent enantioselectivity (2a ~ 2f). The absolute configuration of the arylation product 2a was found to be (R) by X-ray crystallography. This is consistent with stereochemical models based on steric repulsion. Electron deficient aryl iodides with trifluoromethoxy, fluoro, chloro, bromo, and iodo substituents are also compatible and consistently give high enantioselectivity (2 h to 2 m), but trifluoromethyl substitution yields The rate dropped to 45% (2 n). Other electron withdrawing functional groups such as, for example, ketones, esters and phosphonates were also compatible, giving the desired enantioselectivity and good yields (2o-2s). Disubstituted aryl iodides have also been found to be suitable coupling partners (2t-2v).

Isolated yield of purified compound. The absolute configuration was determined by X-ray crystallography.

  It is preferred that this protocol for the enantioselective arylation of methylene C—H bonds has also been found to be applicable to other aliphatic amides (Table 8 below). Thus, aliphatic amides of various chain lengths were well tolerated with excellent enantioselectivity and high yields (4a-4d).

^* Isolated yield of purified compound. The absolute configuration was determined by X-ray. ^* Compound 4t~4w is 1.5 equivalents of Ag ₂ CO _3, 2.5 were obtained using L32 as an equivalent amount of an aryl iodide and a ligand. Phth = phthalimido group; Ts = toluenesulfonyl.

As evident from the data in Table 8, substrates containing sterically hindered alkyl groups (cyclopentyl, clyclohexyl) in the beta position gave good enantioselectivity but gave lower yields (4e, 4f ). Isopropyl, cyclopentyl, cyclohexyl and cyclohexylmethyl at the gamma position were well tolerated and gave satisfactory yields and enantioselectivity (4 g to 4 j). The phenyl, ester, amino, ether and ketone functionalities at the δ and ε positions consistently gave high enantioselectivity (4k-4p). However, lower yields were obtained with ether and ketone substrates (4o, 4p).
The piperidine at the gamma position provided good yields and high enantioselectivity (4q), while the presence of the piperidine at the beta position gave lower yields (4r). The presence of the tetrahydropyran motif at the gamma position is also well tolerated and results in synthetically useful yields and enantioselectivities (4s).
Interestingly, the arylation of benzyl CH with 3t using ligand L35 resulted in poor yield and enantioselectivity (38% yield, 68:32 er). The switch to ligand L32 significantly improved both yield and enantioselectivity (4 t). The β-phenyl group containing both electron-withdrawing and electron-donating groups is also compatible with this reaction (4u-4w), and as a result this ligand scaffold is also used for enantioselective activation of the benzylic CH bond I demonstrated that I could do it.
In summary, it can be seen that the chiral bidentate acetyl protected aminoethyl quinoline ligand scaffold allows for palladium-catalyzed enantioselective arylation of β-methylene CH bonds.
As mentioned earlier, contemplated ligands may be quinolones (which are preferred), pyridines or imidazolines. A study with an imidazoline (imidazolilne) ligand of formula A-4 is shown below.

Chiral mono-protected aminomethyl oxazoline (MPAO) ligands as indicated above are Pd (II) catalyzed enantioselective β-arylation, β-alkenylation, and β-alkynylation of isobutyric acid amides as described below Make it possible to The remaining α-methyl groups can then be subjected to further CH functionalization, leading to greater product diversity.
2-aminoisobutyric acid derived with direct access to a wide range of enantioenriched α, α-dialkyl α-amino acids that can be used as a basic unit for peptide based drug synthesis using chiral benzoyl protected aminomethyl oxazoline ligands Asymmetry of the amide (5) has also been introduced [Venkatraman et al., Chem. Rev. 101, 3131-3152 (2001); Sagan et al., Curr. Med. Chem. 11, 2799-2822 (2004). ]. Systematic ligand modification suggests that further interaction of the chiral center on the oxazoline ring with the substrate is important for the success of the asymmetry of the isopropyl group.

Initial attempts by the inventors and co-workers to asymptize the isopropyl group of the isobutyric acid-derived substrate focused on the use of chiral adjuvants [Giri et al., Angew. Chem. Int. Ed. 44, 2112-2115 (2005); Giri et al., Angew. Chem. Int. Ed. 44, 7420-7424 (2005)]. These studies are based on the isolation and computational analysis of chiral CH insertion intermediates as revealed in detail [Musaev et al., J. Am. Chem. Soc. 134, 1690-1698 (2012); Giri et al. , J. Am. Chem. Soc. 134, 14118-14126 (2012)], improved the understanding of how it may be possible to achieve chiral discrimination of α-gem-dimethyl groups.
The difficulty in asymmetrizing the gem-dimethyl group in isobutyric acid-derived substrates is demonstrated by the fact that diastereoselectivity is not obtained even when bulky oxazolines are used as chiral adjuvants [Giri et al. , Angew. Chem. Int. Ed. 44, 2112-2115 (2005)]. Furthermore, asymmetry of the α-dimethyl group using chiral amino acid derived ligands succeeds only when the α-hydrogen atom is replaced by the extremely bulky α-tert-butyl group (90: 10 er) [Xiao et al., J. Am. Chem. Soc. 136, 8138-8142 (2014)]. The use of chiral phosphate ligands also failed to confer enantioselectivity for the asymmetry of the gem-dimethyl group in isobutyric acid derived substrates [Engle et al., J. Org. Chem. 78, 8927-8955 (2013); Yan et al., Org. Lett. 17, 2458-2461 (2015); Jain et al., Nat. Chem. 134, 14118-14126 (2016); Wang et al., Angew. Chem. Int. Ed. 55, 15387-15391 (2016)].

Development of bidentate chiral acetyl-protected aminoethyl quinoline (APAQ, eg L35) ligands for enantioselective methylene CH activation makes these ligands useful for the asymmetrization of the isopropyl group of isobutyric acid derived amides It prompted a test whether it turned out [Chen et al., Science 353, 1023-1027 (2016)]. With isobutyric acid amide substrate 3, L35 gave almost a racemic product. Furthermore, extensive modification of the APAQ ligand did not lead to a remarkable improvement of the enantiomeric ratio (er) by this group of substrates.
This result highlights the difference between the asymmetry of the isopropyl group and the enantioselective methylene CH activation. In order to amplify the steric interaction between substrate and catalyst, the quinoline motif was replaced with an oxazoline moiety, thereby enabling the introduction of an additional chiral bias to the catalyst. L63 consisting of an achiral oxazoline moiety, a bulky isopropyl stereocenter (derived from valine), and an N-acetyl protected amine failed to achieve significant stereoinduction. In addition, the chiral oxazoline ligand L64, which is derived from N-acetylglycine and consequently lacks a stereocenter in the ligand backbone, also failed to provide an enantioenriched product.
Interestingly, the combination of the two C-4 chiral centers on the oxazoline with the side chain in L82 yielded a promising er of 85:15. Increasing the steric bulk on the side chain (ie, isopropyl to tert-butyl, L 61) further improved the stereoselectivity to an er of 98: 2. The synergy of these two related stereocenters is evident from the complete loss of enantioselectivity when reversing the absolute stereochemistry of one of the chiral centers, as shown by L83. These results are shown in Table 9 below with further details.

While a complete rational description of the observed chiral induction requires extensive computer and kinetic analysis, the absolute configuration of the product and the observed effects of each chiral center on the ligand are steric interactions Match with It is proposed that the N-acetyl group on the coordinating nitrogen is oriented at the top of the square plane of palladium for steric repulsion with the chiral center on the side chain. The 4-benzyl group on the oxazoline ring further shields the top of the intermediate. These combined steric interactions can enhance the orientation of the α-methyl group in the intermediate, thereby establishing the stereochemistry of the CH cleavage step.
Using the optimal chiral ligand and the conditions at hand, we screened the enantioselective β-CH arylation of isobutyric acid amide 3 with a wide variety of aryl iodides. Para-substituents on aryl iodides ranging from electron donating groups (OMe, NBnBoc) to electron withdrawing groups (halides, CF ₃ , keto and nitro) are tolerated and enantiomeric to 98: 2 er Provides selectivity (4a-4q). The range of meta-substituted aryl iodides is also broad, with enantiomeric ratios greater than 94: 6 obtained (4r-4ab). Interestingly, the above ranges of ortho, meta and para substituted aryl iodides are halogen (as in 4l to 4n, 4u to 4w and 4ah) or reactive groups (phosphonate moiety at 4i and aldehyde functionality at 4aa and 4ae) This is characterized either, which can serve as a synthetic handle useful for subsequent chemical manipulations. Some heteroaryl iodides, including thiophene, benzothiophene and indole moieties, are also compatible and give products with high enantioselectivity in synthetically useful yields (4al to 4ap). The simplicity of deprotecting the amide adjuvant with BF ₃ .Et ₂ O was also demonstrated with product 4q without loss of enantioselectivity. These results are shown in detail in Table 10 below.

Data are reported as isolated yields for each entry number. ^* = 10 mol% L89, Ar-I, Ag 2 CO 3, toluene, 50 ° C., 72 hours. ^† = 96 hours. Ar _F = 4- (CF ₃ ) C ₆ F ₄ ; p-Tol-I = para-tolyl iodide; equiv. = Equivalent; Et = ethyl group; Ph = phenyl group; Ac = acetyl group; Ar (Het) = ( Hetero) aryl group; TBS = tert-butyldimethylsilyl group; Bn = benzyl group; Boc = tert-butyloxycarbonyl group; Ts = tosyl group; Phth = phthalimido group; HFIP = hexafluoro-2-propanol.

Unique pharmacological and conformational properties of α, α-disubstituted α-amino acids exhibited in peptide drug molecules [Venkatraman et al., Chem. Rev. 101, 3131-3152 (2001); Sagan et al., Curr. Med. Chem. 11, 2799-2822 (2004)] facilitated the application to N-phthaloyl protected 2-amino-isobutyric acid derivatives. However, analogous amide substrates prepared by the condensation of N-Phth protected 2-aminoisobutyric acid and 2,3,5,6-tetrafluoro-4- (trifluoromethyl) aniline are probably capable of blocking coordination. It does not react under these conditions due to the steric bulk of the substrate. In order to reduce the steric hindrance of the substrate, N-methoxyamide 7 of N-phthaloyl protected 2-amino-isobutyric acid was prepared [Chen et al., J. Am. Chem. Soc. 137, 3338-3351 (2015) Zhu et al., Angew. Chem. Int. Ed. 55, 10578-10599 (2016)].
7 showed substantial degradation under the conditions established for substrate 3, but with milder conditions it was found that β-arylation can proceed at 35 ° C. The ligand L61 gave satisfactory enantioselectivity (91: 9 er), but the yield remained low (about 40% yield) despite extensive optimization.
Thereafter, the MPAO ligand was screened. Modification of the oxazoline ring and amino acid side chain only results in a modest improvement in yield, but substitution of the N-acetyl moiety with the ortho-difluorobenzoyl group (L100), high enantioselectivity (er of 96: 4) While maintaining, the yield of 8b was increased to 75%. CH coupling with various aryl iodides resulted in the accessibility of access to enantioenriched α, α-disubstituted α-amino acids containing chiral α-quaternary centers (8a-8r).
The facile conversion of the N-methoxyamide adjuvant to the ester facilitated this method [Chen et al., J. Am. Chem. Soc. 137, 3338-3351 (2015)]. On a gram scale, both the N-methoxyamide adjuvant and the phthaloyl (phth) protecting group were removed and converted to Fmoc protected amino acids to be used in the peptide drug discovery program.
These results using amino protected and carboxy protected 2-aminobutyric acid as a substrate are shown in Table 11 below.

^† = 96 hours.

One potential advantage of the organometallic approach to the enantioselective functionalization of C (sp ³ ) -H bonds is that metallated intermediates can be reactive with various coupling partners is there. Unfortunately, Pd-catalyzed enantioselective C (sp ³ ) -H activation reactions have been limited to the prior art arylation. In order to fully realize the potential of the asymmetric metal insertion process, three enantioselective CH alkenylation and alkynylation reactions were developed.
Β-Styrenylation of amide 3 using chiral ligand 61 gave the product 88:12 er. The use of L89 containing an additional chiral center at C-5 improved the enantioselectivity to a 94: 6 er.
Several (E) -styrenyl iodides are compatible coupling partners (9a to 9s), including disubstituted (E) -styrenyl iodides (9t). The use of other simple (E) -alkenyl iodides also gave good enantioselectivity, albeit at low yields (5u, 5v). With slight changes in reaction conditions, the use of L89 also allowed the enantioselective β-alkynylation to proceed at an 94.5: 5.5 er (10). The results are shown in Table 12 below.

  Arylation (11a-11f), alkynylation (12), alkylation (13), bromination (14), and boron to further broaden the diversity of chiral centers accessed by these three enantioselective transformations Subsequent β-functionalization of the remaining methyl groups was carried out, including formula (15). Thus, subsequent CH functionalization of the isopropyl group with a wide variety of coupling partners has resulted in myriad alpha-chiral carboxylic acids. The results are shown in Table 13 below.

Ar _F = 4- (CF ₃ ) C ₆ F ₄ ; Et = ethyl group; Ph = phenyl group; Ts = tosyl group; Bpin = pinacolylboronate group, ag. = Aqueous; rt. = Room temperature. Data are reported as isolated yields for each entry number. Reagents and conditions: (a) H ₂ O ₂ , aqueous buffer (pH = 7), THF, rt. (B) 10 mol% of Cu (OAc) ₂ , NHEtPh, Ag ₂ CO ₃ , toluene, 100 ° C.

Materials and Methods General Information Solvents were obtained from Sigma-Aldrich, Alfa-Aesar, Oakwood and Acros and used as such without further purification. _{Pd (CH 3 CN) 4 (} OTf) 2 _{is, Pd (OAc) 2 (Strem} Chemicals 46-1781) and were synthesized in acetonitrile trifluoromethane sulfonic acid (Acros 169890500) [Drent et al ., J. Organomet. Chem. 1991, 417: 235]. Bis (pinacolato) diboron was purchased from Matrix Scientific (101787-966). Carboxylic acids or carboxylic acid chlorides and 2,3,5,6-tetrafluoro-4- (trifluoromethyl) anilines are obtained from commercial sources or prepared according to the procedures of the following document and used for the preparation of the corresponding amides It was.
Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-F254. Visualization was done using UV light and Vogel's permanganate.
¹ H NMR spectra were recorded on a Bruker DRX-600 instrument (400 MHz or 600 MHz). Chemical shifts are estimated in parts per million (ppm) relative to 0.0 ppm of tetramethylsilane. The following abbreviations (or combinations thereof) were used to illustrate multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, sep = sevenet, m = multiplet, br = wide line. Coupling constants J were reported in Hertz (Hz). ^{The 13} C NMR spectra were recorded on a Bruker DRX-600 instrument (150 MHz) and completely decoupled by broadband proton decoupling. Chemical shifts were reported relative to the center line of the multiplet of 29.8ppm whether or acetone -d ₆ referenced to center line of the triplet of 77.0ppm chloroform -d. ^{In the 13} C NMR analysis, the peaks corresponding to the peaks of the polyfluoroarylamide auxiliary appeared as a nearly invisible complex multiplet group, but they are omitted in the following spectral analysis. ¹⁹ F NMR spectra were recorded on a Bruker AMX-400 instrument (376 MHz).
Melting points were recorded on a Fisher-Johns 12-144 melting point apparatus. High resolution mass spectra (HRMS) were recorded on an Agilent Mass spectrometer using ESI-TOF (electrospray ionization-time of flight). Enantiomeric excess values (er) were determined using a commercially available chiral column on a Hitachi LaChrom Elite® HPLC system. Optical rotation data were obtained on a Perkin-Elmer 341 polarimeter.
Substrate preparation

General procedure for amide preparation
Acid chloride (1 equivalent) prepared from the corresponding carboxylic acid and oxalyl chloride is stirred vigorously in toluene (1 M) 2,3,5,6-tetrafluoro-4- (trifluoromethyl) aniline (Ar _F ) To a solution of NH ₂ ) (1.1 eq.) Was added. The reaction mixture was stirred under reflux for 12 hours and then cooled to room temperature. The product mixture was concentrated in vacuo and recrystallized from ethyl acetate / hexane to give the desired amide. ^{In the 13} C NMR analysis, the peaks corresponding to the peaks of the polyfluoroarylamide auxiliary appeared as a nearly invisible complex multiplet group, but they are omitted in the following spectral analysis.

N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) butyramide (1)
¹ H NMR (600 MHz, CDCl ₃ ) δ 6.99 (br s, 1 H), 2.47 (t, J = 7.4 Hz, 2 H), 1.83-1. 76 (m, 2 H), 1.04 (t, J = 7.4 Hz, 3 H ).

N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) pentanamide (3a)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.07 (br s, 1 H), 2.48 (t, J = 7.8 Hz, 2 H), 1.75-1.71 (m, 2 H), 1.45-1.41 (m, 2 H), 0.96 (t, J = 7.4 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.79, 36.09, 27.34, 22.13, 13.68.

N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) hexanamide (3b)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.17 (br s, 1 H), 2.48 (t, J = 7.8 Hz, 2 H), 1.76-1.73 (m, 2 H), 1.38-1 .35 (m, 4 H), 0.92 (t, J = 7.4 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.92, 36.32, 31.17, 25.01, 22.31, 13.83.

N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) octanamide (3c)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.11 (br s, 1 H), 2.48 (t, J = 7.8 Hz, 2 H), 1.77-1.72 (m, 2 H), 1.41-1.26 (m, 8 H), 0.90 -0.88 (m, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.85, 36.38, 31.61, 28.99, 28.92, 25.33, 22.56, 14.01.

N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) tetradecane amide (3d)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.00 (br s, 1 H), 2.48 (t, J = 7.5 Hz, 2 H), 1.75-1.73 (m, 2 H), 1.40-1.24 (m, 20 H), 0.88 (t, J = 7.0 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.72, 36.41, 31.91, 29.62, 29.56, 29.35, 29.26, 29.26, 29.25, 29.04, 25.33, 22.68, 14.10.

3-Cyclopentyl-N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) propanamide (3e)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.20 (br s, 1 H), 2.49 (t, J = 7.9 Hz, 2 H), 1.84-1.74 (m, 5 H), 1.65-1.61 (m, 2 H), 1.58 -1.35 (m, 2H), 1.15-1.11 (m, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 171.03, 39.57, 35.69, 32.41, 31.48, 25.10.

3-Cyclohexyl-N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) propanamide (3f)
¹ H NMR (600 MHz, CDCl ₃ ) δ 6.96 (br s, 1 H), 2.49 (t, J = 7.9 Hz, 2 H), 1.75-1.63 (m, 7 H), 1.33-1.14 (m, 4 H), 0.97 -0.91 (m, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.94, 37.19, 33.96, 32.99, 32.62, 26.42, 26.15.

5-Methyl-N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) hexanamide (3 g)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.12 (br s, 1 H), 2.46 (t, J = 7.5 Hz, 2 H), 1.75-1.73 (m, 2 H), 1.62-1.57 (m, 1 H), 1.29 -1.25 (m, 2H), 0.91 (d, J = 6.7 Hz, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.83, 38.21, 36.58, 27.79, 23.20, 22.41.

4-Cyclopentyl-N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) butanamide (3h)
¹ H NMR (600 MHz, CDCl ₃ ) δ 6.98 (br s, 1 H), 2.48 (t, J = 7.5 Hz, 2 H), 1.80-1. 74 (m, 5 H), 1.65-1. 47 (m, 4 H), 1.42 -1.38 (m, 2H), 1.12-1.06 (m, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.68, 39.82, 36.64, 35.51, 32.60, 25.13, 24.55.

4-Cyclohexyl-N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) butanamide (3i)
¹ H NMR (600 MHz, CDCl ₃ ) δ 6.98 (br s, 1 H), 2.46 (t, J = 7.5 Hz, 2 H), 1.80-1.63 (m, 7 H), 1.29-1.11 (m, 6 H), 0.93 -0.86 (m, 2 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.71, 37.39, 36.78, 36.69, 33.22, 26.60, 26.29, 22.75.

5-Cyclohexyl-N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) pentanamide (3j)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.19 (br s, 1 H), 2.47 (t, J = 7.5 Hz, 2 H), 1.74-1.62 (m, 7 H), 1.42-1.36 (m, 2 H), 1.25 -1.11 (m, 6H), 0.91-0.83 (m, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.94, 37.45, 37.07, 36.38, 33.33, 26.66, 26.35, 26.28, 25.64.

5-phenyl-N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) pentanamide (3k)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.30-7.27 (m, 2H), 7.20-7.17 (m, 3H), 6.99 (s, 1H), 2.67 (t, J = 7.4 Hz, 2H), 2.48 ( t, J = 7.3 Hz, 2 H), 1.82-1.70 (m, 4 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.47, 141.79, 128.39, 128.36, 125.92, 36.15, 35.55, 30.68, 24.85.

Methyl 8-oxo-8-((2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) amino) octanoate (3 l)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.54 (br s, 1 H), 3.67 (s, 3 H), 2.48 (t, J = 7.5 Hz, 2 H), 2. 33 (t, J = 7.4 Hz, 2 H), 1.79-1.72 (m, 2H), 1.67-1.62 (m, 2H), 1.44-1.33 (m, 4H). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 174.39, 170.94, 51.54, 35.97, 33.82, 28.47, 28.40, 24.98, 24.52.

Methyl 9-oxo-9-((2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) amino) nonanoic acid (3 m)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.29 (br s, 1 H), 3.67 (s, 3 H), 2.48 (t, J = 7.5 Hz, 2 H), 2. 32 (t, J = 7.4 Hz, 2 H), 1.79-1.71 (m, 2H), 1.65-1.61 (m, 2H), 1.43-1.31 (m, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 174.40, 170.78, 51.50, 36.20, 33.95, 28.72, 28.70, 28.62, 25.11, 24.69.

6- (1,3-dioxoisoindoline-2-yl) -N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) hexanamide (3n)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.82 (dd, J ₁ = 3.1 Hz, J ₂ = 5.4 Hz, 2 H), 7.71 (dd, J ₁ = 3.0 Hz, J ₂ = 5.5 Hz, 2 H), 7.26 (br s, 1 H), 3.72 (t, J = 7.1 Hz, 2 H), 2.50 (t, J = 7.4 Hz, 2 H), 1.86-1.81 (m, 2 H), 1.78-1.73 (m, 2 H), 1.49 -1.44 (m, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.41, 168.54, 133.98, 132.01, 123.17, 37.41, 35.98, 27.97, 25.85, 24.54.

6-Methoxy-N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) hexanamide (3o)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.63 (br s, 1 H), 3.41 (t, J = 6.4 Hz, 2 H), 3.34 (s, 3 H), 2.48 (t, J = 7.4 Hz, 2 H), 1.79-1.74 (m, 2H), 1.65-1.60 (m, 2H), 1.49-1.44 (m, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 171.00, 72.49, 58.48, 36.01, 29.04, 25.55, 25.05.

N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) pentanamide (3p)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.96-7.91 (m, 2H), 7.58-7.55 (m, 1H), 7.48-7.45 (m, 2H), 7.31 (br s, 1H), 3.03 (t, J = 7.0 Hz, 2 H), 2.54 (t, J = 7.3 Hz, 2 H), 1.85-1. 79 (m, 4 H), 1.53-1. 48 (m, 2 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 200.48 , 170.68, 136.85, 133.15, 128.62, 128.00, 38.05, 35.84, 28.33, 25.05, 23.23.

N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) -4- (1-tosylpiperidin-4-yl) butanamide (3q)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.61-7.58 (m, 3 H), 7.33-7.30 (m, 2 H), 3.75-3. 71 (m, 2 H), 2.45- 2.43 (m, 5 H), 2.23-2.17 (m, 2H), 1.76-1.66 (m, 4H), 1.32-1.24 (m, 4H), 1.23-1.15 (m, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.78, 143.62, 132.81, 129.60, 127.58, 46.39, 36.14, 35.39, 34.91, 31.36, 22.34, 21.46.

N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) -3- (1-tosylpiperidin-4-yl) propanamide (3r)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.61 (d, J = 8.0 Hz, 2 H), 7.50 (br s, 1 H), 7.32 (d, J = 7.9 Hz, 2 H), 3.77-3.75 (m, 2 H) ), 2.48-2.44 (m, 2H), 2.42 (s, 3H), 2.24-2.20 (m, 2H), 1.78-1.75 (m, 2H), 1.71-1.65 (m, 2H), 1.37-1.26 (m) , 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.55, 143.72, 132.75, 129.66, 127.58, 46.30, 34.37, 33.08, 31.14, 31.09, 21.49.

N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) -4- (tetrahydro-2H-pyran-4-yl) butanamide (3s)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.54 (br s, 1 H), 3.97-3.94 (m, 2 H), 3.38 (dt, J ₁ = 2.1 Hz, J ₂ = 11.9 Hz, 2 H), 2.47 (t , J = 7.4 Hz, 2H), 1.79-1.74 (m, 2H), 1.63-1.60 (m, 2H), 1.54-1.48 (m, 1H), 1.35-1.22 (m, 4H); ¹³ C NMR (150) MHz, CDCl ₃ ) δ 170.74, 67.99, 36.27, 36.23, 34.76, 32.95, 22.16.

3-phenyl-N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) propanamide (3t)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.34-7.30 (m, 2 H), 7.26-7.23 (m, 3 H), 3.07 (t, J = 7.4 Hz, 2 H), 2.79 (t, J = 7.5 Hz, 2H).

Methyl 4- (3-oxo-3-((2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) amino) propyl) benzoate (3u)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.98 (d, J = 8.3 Hz, 2 H), 7.30 (d, J = 8.3 Hz, 2 H), 6.99 (br s, 1 H), 3.91 (s, 3 H), 3.13 (t, J = 7.4 Hz, 2 H), 2.81 (t, J = 7.4 Hz, 2 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.29, 166.97, 145.27, 130.05, 128.61, 128.43, 52.11, 37.53 , 31.02.

N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) -3- (m-tolyl) propanamide (3v)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.21 (t, J = 7.8 Hz, 1 H), 7.06-7.03 (m, 3 H), 6.88 (br s, 1 H), 3.03 (t, J = 7.4 Hz, 2 H ), 2.78 (t, J = 7.4 Hz, 2 H), 2. 34 (s, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.88, 139.68, 138.48, 129.12, 128.69, 127.43, 125.25, 38.18, 31.17, 21.34.

3- (3-Bromophenyl) -N- (2,3,5,6-tetrafluoro-4- (trifluoromethyl) phenyl) propanamide (3w)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.40-7.39 (m, 1 H), 7.38-7.36 (m, 1 H), 7.20-7.16 (m, 2 H), 6.92 (br s, 1 H), 3.04 (t, J = 7.4 Hz, 2 H), 2. 78 (t, J = 7.5 Hz, 2 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.33, 142.11, 131.36, 130.29, 129.82, 127.08, 122.73, 30.69.

Ligand preparation Ligand L2 [Geissman et al., J. Org. Chem. 24, 41-43 (1959)], L3 (bromide L5-1) [Wang et al., Nature 519, 334-338 ( 2015)], L6 [Jordan et al., Heterocycles 33, 657-671 (1992)], and L9 [Here et al., WIPO WO2014 / 140184 A1 (2014)] were prepared according to the procedure of the following document.
Synthesis of ligand L4:

Synthesis of L4-1:
To a solution of diisopropylamine (1.01 g, 1.4 mL, 10 mmol) in 10 ml of THF at −78 ° C. under nitrogen was added n-butyllithium (2.5 M in hexane, 4 mL, 10 mmol) dropwise. After 30 minutes, HMPA (1.79 g, 1.74 mL, 10 mmol) was added to this solution. The resulting solution was treated with 2-chloro-3-methylquinoline (1.78 g, 10 mmol) in THF (10 mL) to give a red solution and stirred for 30 minutes. To this mixture was added 3,5-bis (tert-butyl) benzaldehyde (1.09 g, 5 mmol) in THF (10 mL) at -78.degree. After 1 hour at −78 ° C., the reaction mixture is quenched with saturated aqueous NH ₄ Cl, treated with 30 ml of diethyl ether and the product is extracted three times with 20 ml aliquots of diethyl ether. The combined extracts were washed with water, dried over anhydrous MgSO ₄ and concentrated in vacuo. Flash chromatography (eluent: dichloromethane) gave alcohol L4-1 (1.40 g, 71% yield) as a yellow foam. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.02-8.00 (m, 1 H), 7.96 (s, 1 H), 7.73 (dd, J ₁ = 1.3 Hz, J ₂ = 8.1 Hz, 1 H), 7.71-7.68 ( m, 1 H), 7.55-7.52 (m, 1 H), 7. 39 (t, J = 1.8 Hz, 1 H), 7.24 (d, J = 1.8 Hz, 2 H), 5. 16 (t, J = 6.6 Hz, 1 H), _{3.33 (dd, J 1 = 3.7} Hz, J 2 = 6.6 Hz, 2H), 1.32 (s, 18H); 13 C NMR (150 MHz, CDCl 3) δ 151.41, 151.08, 146.62, 142.73, 139.71, 130.35, 129.87 , 128.09, 127.31, 127.13, 126.92, 121.91, 119.85, 73.65, 43.37, 34.88, 31.42.

Synthesis of L4-2a and L4-2b:
CH ₂ Cl ₂ (10mL) solution of Ac-Phe-OH (311mg, 1.5mmol), DMAP (183mg, 1.5mmol) and DCC (309mg, 1.5mmol) alcohol L4-1 mixture of (300 mg, 0.75 mmol) added. The mixture was stirred at room temperature for 18 hours. The resulting suspension was filtered using a funnel packed with Celite® to obtain a clear solution. After removing the solvent under vacuum, the crude product was separated by preparative TLC (eluent: dichloromethane / acetone = 10/1) to give two diastereomeric esters: L4-2a (white solid, Low polarity, 197 mg, 45% yield) and L4-2b (white solid, high polarity, 189 mg, 43% yield). L4-2a: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98-7.96 (m, 1 H), 7.79 (s, 1 H), 7. 70-7. 63 (m, 2 H), 7.51-7. 47 (m, 1 H), 7.34 (t, J = 1.8 Hz, 1 H), 7. 10-7.0 4 (m, 5 H), 6. 78 (dd, J ₁ = 2.0 Hz, J ₂ = 7.3 Hz, 2 H), 6. 10 (dd, J ₁ = 5.7 Hz, J ₂ = 8.4 Hz, 1 H), 5. 91 (d, J = 7.9 Hz, 1 H), 4.91 (dt, J ₁ = 5.9 Hz, J ₂ = 7.9 Hz, 1 H), 3.50 (dd, J ₁ = 8.4 Hz, J ₂ = 14.1 Hz, 1 H), 3.27 (dd, J ₁ = 5.7 Hz, J ₂ = 14.1 Hz, 1 H), 3.05 (dd, J ₁ = 6.5 Hz, J ₂ = 13.8 Hz, 1 H), 2. 95 (dd, J ₁ = 5.5 Hz, J ₂ = 13.8 Hz, 1 H), 1. 88 (d, J = 1.0 Hz, 3 H), 1.25 (s, 18 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.77, 169.29, 151.09 , 151.04, 146.72, 139.68, 135.40, 130.19, 128.61, 128.27, 128.12, 127.08, 126.94, 126.87, 122.41, 120.28, 76.81, 53.06, 40.53, 37.08, 34.76, 31.29, 22.96. L4-2b: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98-7.95 (m, 1 H), 7.80 (s, 1 H), 7.72-7. 65 (m, 2 H), 7.54-7. 49 (m, 1 H), 7.41 _{(dt, J 1 = 1.1 Hz} , J 2 = 1.9 Hz, 1H), 7.19 (d, J = 1.8 Hz, 2H), 7.08-7.00 (m, 3H), 6.74-6.71 (m, 2H), 6.21 ( dd, J = 8.4, 5.1 Hz, 1 H), 5. 79 (d, J = 8.0 Hz, 1 H), 4. 98-4. 76 (m, 1 H), 3.51 (dd, J ₁ = 8.4 Hz, J ₂ = 14.3 Hz, 1 H , 3.42 (dd, J ₁ = 5.2 Hz, J ₂ = 14.3 Hz, 1 H), 3.11 (dd, J ₁ = 6.0 Hz, J ₂ = 13.9 Hz, 1 H), 2. 96 (dd, J ₁ = 5.2 Hz, _{J 2 = 13.9 Hz, 1H)} , 1.81 (s, 3H), 1.28 (d, J = 0.7 Hz, 18H); 13 C NMR (100 MHz, CDCl 3) δ 170.65, 169.36, 151.20, 146.66, 139.42, 137.59 , 135.26, 130.09, 129.21, 128.74, 128.22, 128.22, 127.11, 127.02, 126.52, 120.87, 76.49, 52.74, 40.19, 37.33, 34.82, 31.36, 22.90.

Synthesis of L4:
A mixture of ester L4-2a (210 mg, 0.36 mmol) and KOH (100 mg, 1.8 mmol) in isopropanol (7 mL) and H ₂ O (7 mL) was heated to 100 ° C. for 24 hours. The solvent was removed under vacuum after the mixture was allowed to cool to room temperature. The residue was added a saturated aqueous solution of NH ₄ Cl, treated with 10 ml of diethyl ether, and the product was extracted three times with 10 ml aliquots of diethyl ether. The combined extracts were washed with water, dried over anhydrous MgSO ₄ and concentrated in vacuo. Flash chromatography (eluent: ethyl acetate / hexane = 1/10) gave the product L4 (100 mg, 77% yield) as a white solid.

2- (3,5-Di-tert-butylphenyl) -2,3-dihydrofuro- [2,3-b] quinolone (L4)
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.90 (dd, J ₁ = 1.1 Hz, J ₂ = 8.5 Hz, 1 H), 7.87 (d, J = 1.7 Hz, 1 H), 7.69 (dd, J ₁ = 1.4 _{Hz, J 2 = 8.1 Hz,} 1H), 7.61-7.59 (m, 1H), 7.42 (t, J = 1.8 Hz, 1H), 7.39-7.36 (m, 1H), 7.30 (d, J = 1.8 Hz, 2H), 5.91 (t, J = 8.5 Hz, 1H), 3.82-3.77 (m, 1H), 3.40-3.36 (m, 1H), 1.33 (s, 18H). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 151.25, 147.03, 139.85, 132.65, 129.08, 127.26, 123.99, 122.29, 122.00, 119.63, 82.76, 36.59, 34.94, 31.43. HRMS (ESI-TOF) calculated for C ₂₅ H ₃₀ NO [M + H] ⁺ : 360.2322; found: 360.2323.
Absolute stereochemistry was not assigned.
Synthesis of ligand L5:

Synthesis of L5-2:
CH ₂ bromide L5-1 in _{Cl 2 (150mL) [Wang et} al., Nature 519, 334-338 (2015)] (5.08g, 20mmol) and 3-chloroperoxybenzoic acid (6.40 g, 77% max) The mixture was stirred at room temperature overnight (about 18 hours). The resulting reaction mixture continued to water (150 mL), was added NaHCO ₃ a (13 g) and Na ₂ CO ₃ (1.5g). The aqueous phase was washed with CH ₂ Cl ₂ (2 × 100 mL) and the organic phases were combined and dried over anhydrous MgSO ₄ . After removal of the solvent under vacuum, the crude product was transferred to a round bottom flask, to which acetic anhydride (20 mL) was added. The mixture was refluxed using an oil bath (145-150 ° C.) for 1 hour. Acetic anhydride was removed by vacuum evaporation and the residue was dissolved in CH ₂ Cl ₂ (50 mL) followed by the addition of water (50 mL), NaHCO ₃ (1.5 g) and Na ₂ CO ₃ (2.5 g). The aqueous phase was washed with CH ₂ Cl ₂ (3 × 30 mL) and the organic phases were combined and dried over anhydrous MgSO ₄ . The solvent was evaporated under vacuum leaving a brown sticky oil. The crude product was purified by flash chromatography (eluent: ethyl acetate / hexane = 1/1) to give acetate L5-2 as a yellow solid (4.80 g, 77% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.06-6.02 (m, 1 H), 4.31-4.28 (m, 2 H), 2.98 (m, 1 H), 2.87-2.71 (m, 3 H), 2.84-2.76 (m , 1 H), 2.08 (s, 3 H), 2.07-1.99 (m, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.56, 161.78, 156.19, 134.80, 132.04, 117.50, 77.80, 67.02, 30.10, 28.88 , 25.74, 21.64, 21.16.

Synthesis of L5-3:
Acetate L5-2 (4.80g, 15.38mmol) was added to the _{K 2 CO 3 (4.35g, 30.77mmol} ) MeOH (80mL) in a mixture of and H ₂ O (80mL). The mixture was stirred at room temperature overnight (about 18 hours). The solvent was removed in vacuo. The residue was dissolved in CH ₂ Cl ₂ (50 mL) and water (50 mL) was added. The aqueous phase was washed with CH ₂ Cl ₂ (3 × 30 mL) and the organic phases were combined and dried over anhydrous MgSO ₄ . The crude product obtained by evaporating the solvent under vacuum was purified by flash chromatography (eluent: ethyl acetate / hexane = 1/2 to 1/1) to obtain alcohol L5-3 as a yellow solid (3.55 g, 85% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.20-5.16 (m, 1H), 4.32-4.26 (m, 2H), 3.01-2.93 (m, 1H), 2.78-2.69 (m, 3H), 2.55-2.46 (m, 1 H), 2.09-1.98 (m, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 161.52, 160.70, 135.11, 130.75, 116.38, 75.18, 67.08, 31.80, 28.53, 25.61, 21.69.

Synthesis of L5-4a and L5-4b:
CH ₂ Cl ₂ (50mL) solution of Ac-Phe-OH (4.35g, 21mmol), DMAP (2.56g, 21mmol) and DCC (4.33g, 21mmol) in a mixture of alcohol L5-3 (1.89g, 7mmol) and added. The mixture was stirred at room temperature for 18 hours. The resulting suspension was filtered using a funnel packed with Celite® to obtain a clear solution. After removal of the solvent under vacuum, the crude product was purified by flash chromatography: was separated by (eluent ethyl acetate _{/ CH 2 Cl 2 = 1/} 1) to afford the two diastereomeric esters: L5-4a (White solid, low polarity, 1.32 g, 41% yield) and L5-4b (white solid, high polarity, 1.29 g, 40% yield).
L 5-4a: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32-7.25 (m, 2 H), 7.24-7.16 (m, 3 H), 6.13 (dd, J ₁ = 3.8 Hz, J ₂ = 7.5 Hz, 1 H ), 5.93 (d, J = 7.9 Hz, 1 H), 4.86 (dt, J ₁ = 5.8 Hz, J ₂ = 7.8 Hz, 1 H), 4.33-4.29 (m, 2 H), 3.19 (dd, J ₁ = 5.5) _{Hz, J 2 = 14.0 Hz,} 1H), 3.08 (dd, J 1 = 5.9 Hz, J 2 = 14.0 Hz, 1H), 3.04-2.94 (m, 1H), 2.87-2.76 (m, 3H), 2.60- 2.51 (m, 1 H), 2.06 (dt, J ₁ = 3.6 Hz, J ₂ = 6.6 Hz, 3 H), 1. 96 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.06, 169.58, 161.82, 155.68, 135.81, 134.79, 132.46, 129.59, 128.43, 126.90, 117.86, 79.06, 67.07, 53.58, 29.83, 28.99, 25.84, 23.12, 21.67.
L 5-4b: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.28-7.19 (m, 3 H), 7.15-7.13 (m, 2 H), 6.30 (d, J = 7.7 Hz, 1 H), 6.07 (dd, J _{1 = 4.0 Hz, J 2 =} 7.5 Hz, 1H), 4.90 (q, J = 6.4 Hz, 1H), 4.28 (t, J = 5.2 Hz, 2H), 3.17-3.07 (m, 2H), 2.94-2.87 (m, 1H), 2.81-2.73 ( m, 3H), 2.53-2.43 (m, 1H), 2.05-1.99 (m, 2H), 1.96 (s, 3H), 1.92-1.84 (m, 1H). 13 _{C NMR (100 MHz, CDCl 3} ) δ 170.93, 169.26, 161.55, 155.26, 135.89, 134.53, 132.02, 129.19, 128.15, 126.69, 117.65, 78.65, 66.84, 53.08, 37.70, 29.44, 28.72, 25.55, 22.88, 21.39.

Synthesis of L5:
To a solution of lithium hydroxide monohydrate (28 mg, 0.66 mmol) in THF (2 mL) and H ₂ O (2 mL) was added ester L 5-4a (100 mg, 0.22 mmol). The mixture was stirred at room temperature overnight (about 18 hours). The mixture was added with aqueous NH ₄ Cl solution and extracted with CH ₂ Cl ₂ . After removing the solvent under vacuum, the crude product was separated by flash chromatography (eluent: ethyl acetate / hexane = 1/1) to obtain alcohol product L5-5 (48 mg, 80% yield) . It has the same ¹ H and ¹³ C NMR spectra as racemate L5-3.
To a solution of alcohol L5-5 (122 mg, 0.45 mmol) in anhydrous THF (3 mL) was added NaH (54 mg, 60% w / w in mineral oil, 1.35 mmol) at 0 ° C. The suspension was stirred for 30 minutes before EtI (350 mg, 0.18 mL, 2.25 mmol) was added. The mixture was allowed to reach room temperature and stirred overnight (about 18 hours). Aqueous NH ₄ Cl solution was added to the mixture and extracted with CH ₂ Cl ₂ . After removing the solvent under vacuum, the crude product L5-6 was used as such for the next step without further purification.
To a solution of crude bromide L5-6 in MeOH (2 mL) was added NaOMe (178 mg, 3.3 mmol) at room temperature. The tube was sealed and heated to 130 ° C. for 72 hours. The reaction mixture was allowed to cool to room temperature and then poured into a saturated aqueous NH ₄ Cl solution. The aqueous phase is extracted with CH ₂ Cl ₂ and the combined organic phases are dried over anhydrous MgSO ₄ . After filtration and removal of the organic solvent under vacuum, the crude product was subjected to preparative TLC separation (eluent: ethyl acetate / hexane = 1/3) to give ether L5 as a pale yellow oil (75 mg, 67 steps over 2 steps % Yield).

8-Ethoxy-5-methoxy-2,3,4,6,7,8-hexahydrocyclopenta [b] pyrano [3,2-e] pyridine (L5)
¹ H NMR (600 MHz, CDCl ₃ ) δ 4.58 (dd, J ₁ = 3.0 Hz, J ₂ = 6.9 Hz, 1 H), 4.26-4.19 (m, 2 H), 3.97 (s, 3 H), 3.88-3.82 ( m, 1H), 3.65 (dq , J 1 = 7.0 Hz, J 2 = 9.4 Hz, 1H), 3.25-3.20 (m, 1H), 2.97-2.91 (m, 1H), 2.62 (q, J = 6.4 Hz , 2H), 2.26-2.20 (m, 1H), 2.09-2.04 (m, 1H), 1.93-1.89 (m, 2H), 1.18 (t, J = 7.0 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 162.41, 161.86, 161.03, 106.08, 81.55, 66.69, 64.82, 58.40, 30.94, 30.92, 27.42, 21.37, 19.56, 15.39; HRMS (ESI-TOF) C ₁₄ H ₁₀ NO ₃ calculated values [M + H] ^< +>: 250.1438; Found: 250.1434.
Absolute stereochemistry was not assigned.

Synthesis of ligand L6 [Jordan et al., Heterocycles 33, 657-671 (1992)]

N- (quinolin-2-ylmethyl) acetamide (L6)
Gray solid ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.14 (d, J = 8.4 Hz, 1 H), 8.06 (dd, J ₁ = 1.0 Hz, J ₂ = 8.3 Hz, 1 H), 7.82 (dd, J _{1 = 1.4 Hz, J 2 = 8.2} Hz, 1H), 7.75-7.72 (m, 1H), 7.56-7.54 (m, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.16 (br s, 1H) , 4.75 (d, J = 4.5 Hz, 2 H), 2.16 (s, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.75, 155.58, 146.79, 136.43, 129.35, 128.28, 127.26, 126.92, 126.00, 119.58 , 44.54, 22.86.

Synthesis of ligand L7:

To a solution of 2-cyanoquinoline (308 mg, 2 mmol) in THF (5 mL) at 0 ° C. was added MeMgBr solution (3 M in ether, 0.73 mL, 2.2 mmol) dropwise. The mixture was stirred at 0 ° C. for 2 h, then MeOH (5 mL) was added after NaBH ₄ (91 mg, 2.4 mmol) was added. The mixture was stirred at room temperature overnight (about 18 hours). The reaction was then quenched with aqueous NH ₄ Cl and extracted with CH ₂ Cl ₂ . The combined extracts were washed with water, dried over anhydrous MgSO ₄ and concentrated in vacuo. The resulting crude amine was dissolved in CH ₂ Cl ₂ (3 mL). To this solution _{Ac 2 O (612mg, 0.58mL,} 6mmol) and _{Et 3 N (606mg, 0.91mL,} 6mmol) was added. The mixture was stirred at room temperature for 18 hours. After removing the solvent by reduced pressure, the crude product was purified by preparative thin layer chromatography (eluent: ethyl acetate / hexane = 1: 2) to give L7 as a white solid (80 mg, 19% over 3 steps) Yield of

N- (1- (quinolin-2-yl) ethyl) acetamide (L7)
¹ H NMR (600 MHz, CDCl ₃ ) δ 8.14 (dd, J ₁ = 0.8 Hz, J ₂ = 8.5 Hz, 1 H), 8.07-8.06 (m, 1 H), 7.82 (dd, J ₁ = 1.4 Hz, J ₂ = 8.0 Hz, 1 H), 7.74-7.71 (m, 1 H), 7.55-7.53 (m, 1 H), 7.43 (br s, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 5. 30-5.25 (m) m, 1 H), 2. 12 (s, 3 H), 1.5 5 (d, J = 6.8 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.36, 160.78, 147.04, 136.86, 129.56, 128.69, 127.53, 127.18 , 126.23, 119.52, 50.08, 23.44 , 22.48; HRMS (ESI-TOF) calcd _{C 13 H 15 N 2 O [} M + H] +: 215.1179; Found: 215.1175.

Synthesis of ligand L8:

To a solution of 2-cyanoquinoline (308 mg, 2 mmol) in THF (5 mL) at 0 ° C. was added dropwise a solution of PhMgBr (1 M in THF, 2.2 mL, 2.2 mmol). The mixture was stirred at 0 ° C. for 2 hours, then MeOH (5 mL) was added after the addition of NaBH ₄ (91 mg, 2.4 mmol). The mixture was stirred at room temperature overnight (about 18 hours). The reaction was then quenched with aqueous NH ₄ Cl and extracted with CH ₂ Cl ₂ . The combined extracts were washed with water, dried over anhydrous MgSO ₄ and concentrated in vacuo. The resulting crude amine was dissolved in CH ₂ Cl ₂ (3 mL). To this solution _{Ac 2 O (612mg, 0.58mL,} 6mmol) and _{Et 3 N (606mg, 0.91mL,} 6mmol) was added. The mixture was stirred at room temperature for 18 hours. After removing the solvent by reduced pressure, the crude product was purified by preparative thin layer chromatography (eluent: ethyl acetate / hexane = 1/2) to give L8 as a yellow solid (95 mg, 17% over 3 steps Yield of

N- (phenyl (quinolin-2-yl) methyl) acetamide (L8)
¹ H NMR (600 MHz, CDCl ₃ ) δ 8.20-8.10 (m, 2 H), 8.04 (dd, J ₁ = 0.8 Hz, J ₂ = 8.5 Hz, ₁ H), 7. 78 (dd, J ₁ = 1.4 Hz, J ₂ = 8.2 Hz, 1 H), 7. 76-7. 73 (m, 1 H), 7.55-7.52 (m, 1 H), 7.42-7. 38 (m, 2 H), 7. 28 (dd, J ₁ = 6.9 Hz, J ₂ = 8.4 Hz , 2H), 7.25 (d, J = 8.5 Hz, 1 H), 7.23-7.20 (m, 1 H), 6.28 (d, J = 6.7 Hz, 1 H), 2.13 (s, 3 H); ¹³ C NMR (150 MHz) , CDCl ₃ ) δ 169.23, 158.34, 146.80, 141.64, 136.69, 129.92, 128.75, 127.59, 127.49, 127.23, 126.50, 120.69, 57.76, 23.43; HRMS (ESI-TOF) C ₁₈ H ₁₇ N ₂ O ₂ Calculated value for [M + H] ⁺ : 277.1336; found: 277.1328.

Synthesis of ligand L9 (32):

N- (2- (quinolin-2-yl) ethyl) acetamide (L9)
Gray solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.10 (dd, J ₁ = 0.8 Hz, J ₂ = 8.4 Hz, 1 H), 8.03-8.02 (m, ₁ H), 7. 80 (dd, J ₁ = 1.4 Hz, J ₂ = 8.1 Hz, 1 H), 7.73-7.69 (m, 1 H), 7.53-7.51 (m, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 6.64 (br s, 1 H), 3.81-3. 78 ( m, 2H), 3.19-3.16 (m, 2H), 1.95 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.98, 160.15, 147.65, 136.61, 129.59, 128.80, 127.63, 126.85, 126.09, 121.79, 38.17, 37.50, 23.45; HRMS (ESI-TOF) calcd _{C 13 H 15 N 2 O [} M + H] +: 215.1179; Found: 215.1182.

Synthesis of ligand L10:

Azodicarboxylic acid in THF (5 mL) in a mixture of alcohol L10-1 (33) (187 mg, 1 mmol), PPh ₃ (393 mg, 1.5 mmol) and phthalimide (220 mg, 1.5 mmol) in THF (5 mL) at 0 ° C. A solution of diethyl (DEAD, 361 mg, 1.5 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 3 hours. The solvent was removed by reduced pressure and the crude product was purified by preparative thin layer chromatography (eluent: ethyl acetate / hexane = 2/3) to give L10-2 as a white solid (270 mg, 85% yield) ). ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.03 (d, J = 8.4 Hz, 1 H), 7. 98 (d, J = 8.5 Hz, 1 H), 7. 78 (dd, J ₁ = 3.1 Hz, J ₂ = 5.4 Hz , 2H), 7.72 (dd, J ₁ = 1.5 Hz, J ₂ = 8.1 Hz, 1 H), 7.67-7.63 (m, 3H), 7.46-7.43 (m, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 3.84 (t, J = 7.0 Hz, 2 H), 3.06-3.04 (m, 2 H), 2.30-2.25 (m, 2 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 168.34, 161.19, 147.82, 136.29, 133.77, 132.05, 129.32, 128.80, 127.41, 126.68, 125.72, 123.05, 121.26, 37.82, 36.39, 28.07.

About L10:
Hydrazine hydrate (117 mg, 2.4 mmol) was added to a suspension of phthalimide L10-2 (150 mg, 0.47 mmol) in EtOH (3 mL) at room temperature. The mixture was heated to 50 ° C. and stirred for 3 hours. The solvent and excess hydrazine were removed to give a white solid. The solid was filtered with CH ₂ Cl ₂ added. The filtrate was concentrated and to the flask was added CH ₂ Cl ₂ (5 mL). Solution _{Ac 2 O (153mg, 0.15mL,} 1.5mmol) and _{Et 3 N (152mg, 0.23mL,} 1.5mmol) was added. The mixture was stirred at room temperature for 18 hours. After removal of solvent, the resulting mixture was filtered and the solid was washed with CH ₂ Cl ₂ . The filtrate is concentrated under vacuum and purified by preparative TLC (eluent: methanol / CH ₂ Cl ₂ = 1/20) to give L10 as a light brown oil (80 mg, 61% yield over 2 steps), It became solid upon standing.

N- (3- (quinolin-2-yl) propyl) acetamide (L10)
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (d, J = 8.4 Hz, 1 H), 8.01 (d, J = 8.6 Hz, 1 H), 7.77 (d, J = 8.1 Hz, 1 H), 7.68 (t , J = 7.7 Hz, 1 H), 7. 49 (t, J = 7.5 Hz, 1 H), 7. 28 (d, J = 8.8 Hz, 1 H), 6. 75 (br s, 1 H), 3.36-3. 32 (m, 2 H), 3.04 (t, J = 7.3 Hz, 2 H), 2.10-2.01 (m, 2 H), 1. 94 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.16, 161.77, 147.49, 136.48, 129.45, 128.31 , 127.48, 126.62, 125.81, 121.41 , 39.28, 36.28, 28.48, 23.14; HRMS (ESI-TOF) C 14 H 17 N 2 calculated ^{O [M + H] +:} 229.1335; Found: 229.1337.

General procedure for the synthesis of L11 to L33

Synthesis of tert-butanesulfinylamines L11-1 to L33-1 [Liu et al., J. Org. Chem. 64, 1278-1284 (1999)]
N-Butyllithium (2.5 M in hexane, 1.8 mL, 4.5 mmol) was added dropwise to a solution of 2-methylquinoline (643 mg, 0.6 mL, 4.5 mmol) in anhydrous THF (5 mL) at 0 ° C. The resulting solution was gradually brought to room temperature and stirred for 3 hours. The mixture was then cooled to −78 ° C. to which was added dropwise enantiomerically pure tert-butanesulfinyl imine (3 mmol) in anhydrous THF (5 mL). The resulting mixture was warmed to 0 ° C. for 2 h and then treated with saturated aqueous NH ₄ Cl. The product was extracted with dichloromethane. The combined extracts were washed with water, dried over anhydrous MgSO ₄ and concentrated in vacuo. Sulfinylamine was purified by column chromatography (eluent: ethyl acetate / hexane = 1/3).

(R) -1-tert-Butyl-1- (λ ¹ -oxydanyl) -N- (1-phenyl-2- (quinolin-2-yl) ethyl) -λ ³ -sulfanamine (L 17-1)
Yellow foam. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.03 (dd, J ₁ = 1.2 Hz, J ₂ = 8.4 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 7. 76 (d, J = 8.0 Hz , 1H), 7.70 (ddd, J ₁ = 1.5 Hz, J ₂ = 6.9 Hz, J ₃ = 8.4 Hz, 1 H), 7. 50 (ddd, J ₁ = 1.2 Hz, J ₂ = 6.9 Hz, J ₃ = 8.1 Hz , ₁ H), 7. 39 (dd, J ₁ = 1.5 Hz, J ₂ = 7.1 Hz, 2 H), 7. 30 (t, J = 7.2 Hz, 2 H), 7.26-7.22 (m, 1 H), 7.11 (d, J = 8.4 Hz, 1 H), 5.02 (dt, J ₁ = 5.3 Hz, J ₂ = 8.0 Hz, 1 H), 4.81 (d, J = 5.1 Hz, 1 H), 3.59 (dd, J ₁ = 8.1 Hz, J ₂ = 14.2 Hz, 1 H), 3.43 (dd, J ₁ = 5.5 Hz, J ₂ = 14.2 Hz, 1 H), 1. 10 (s, 9 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 158.82, 147.64, 141.84, 136.24 , 129.53, 128.79, 128.53, 127.67, 127.53, 127.29, 126.77, 126.05, 122.23, 59.30, 56.10, 46.13, 22.47.

(R) -1-tert-Butyl-N- (1- (3,5-di-tert-butylphenyl) -2- (quinolin-2-yl) ethyl) -1- (λ ¹ -oxydanyl) -λ ^3- sulfanamine (L32-1)
Yellow foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (dd, J ₁ = 1.0 Hz, J ₂ = 8.4 Hz, 2 H), 7.82 to 7.73 (m, 2 H), 7.57 to 7.53 (m, 1 H), 7.34- 7.32 (m, 2H), 7.26 (s, 1H), 7.16 (d, J = 8.4 Hz, 1 H), 5.06 (dt, J ₁ = 5.2 Hz, J ₂ = 9.1 Hz, 1 H), 4.65 (d, J = 4.5 Hz, 1 H), _3. 65 (dd, J ₁ = 8.3 Hz, J ₂ = 14.0 Hz, 1 H), _3. 48 (dd, J ₁ = 5.5 Hz, J ₂ = 14.0 Hz, 1 H), 1.32 (s, 18 H ), 1.14 (s, 9H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 159.14, 150.80, 147.68, 140.95, 136.10, 129.48, 128.80, 127.48, 126.79, 126.00, 122.27, 121.55, 121.44, 59.64, 56.06 46.57, 34.85, 31.41, 22.49.HRMS calculated _{(ESI-TOF) C 29 H} 41 N 2 OS [M + H] +: 465.2934; Found: 465.2934.

Synthesis of L11-L33 To a solution of tert-butanesulfinylamine (1 equivalent) in MeOH at room temperature was added a solution of HCl (4 N in dioxane, 4 equivalents). The mixture was stirred for 6 hours before removing the solvent under vacuum. To the resulting foam was added CH ₂ Cl ₂ and Et ₃ N (4 equivalents) at room temperature followed by acetic anhydride (4 equivalents). The mixture was stirred overnight (about 18 hours) and then treated with saturated aqueous Na ₂ CO ₃ solution. The product was extracted with dichloromethane. The combined extracts were washed with water, dried over anhydrous MgSO ₄ and concentrated in vacuo. Flash chromatography gave the ligand as a white solid or colorless oil.

(S) -N- (1- (Quinolin-2-yl) propan-2-yl) acetamide (L11)
White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.11 (d, J = 8.4 Hz, 1 H), 8.02 (d, J = 8.5 Hz, 1 H), 7.81 (d, J = 8.1 Hz, 1 H), 7.71 (t , J = 7.7 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 6.78 (br s, 1 H), 4.47 (t, J = 6.7 Hz, 1H), 3.19 (dd, J 1 = 5.3 Hz, J 2 = 14.0 Hz, 1H), 3.07 (dd, J 1 = 6.7 Hz, J 2 = 13.9 Hz, 1H), 1.92 (s, 3H), 1.21 ( d, J = 6.6 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.32, 159.47, 147.56, 136.62, 129.62, 128.77, 126.84, 126.12, 122.25, 45.33, 44.11, 23.57, 20.43; HRMS _{(ESI-TOF) C 14 H} 17 N 2 calculated ^{O [M + H] +:} 229.1335; Found: 229.1336.
Absolute stereochemistry was assigned by similarity to compound L13.

(S) -N- (1- (quinolin-2-yl) butan-2-yl) acetamide (L12)
White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.09 (d, J = 8.4 Hz, 1 H), 8.01-8.00 (m, 1 H), 7.79 (dd, J ₁ = 1.4 Hz, J ₂ = 8.1 Hz, 1 H) , 7.71-7.69 (m, 1H), 7.52-7.50 (m, 1H), 7.33 (d, J = 8.4 Hz, 1 H), 6.67 (d, J = 8.5 Hz, 1 H), 4.34-4.30 (m, 1 H) _{), 3.20 (dd, J 1} = 5.0 Hz, J 2 = 14.2 Hz, 1H), 3.08 (dd, J 1 = 7.1 Hz, J 2 = 14.1 Hz, 1H), 1.91 (s, 3H), 1.58-1.53 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.13, 159.24, 147.06, 136.16, 129.14, 128.25, 127.21, 126.37, 125.62, 121.70, 50.28 , 41.53, 27.04, 23.09, 10.10 ; HRMS (ESI-TOF) calcd _{C 15 H 19 N 2 O [} M + H] +: 243.1492; Found: 243.1489.
Absolute stereochemistry was assigned by similarity to compound L13.

(S) -N- (1- (Quinolin-2-yl) pentan-2-yl) acetamide (L13)
White solid, [α] _D ²⁰ = -70.5 (c = 0.89, CHCl ₃ ). Melting point = 129-131 ° C. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.10-8.09 (m, 1 H), 8.02-8.00 (m, 1 H), 7.81-7.79 (m, 1 H), 7.72-7.69 (m, 1 H), 7.53-7.50 (m, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 6. 65 (d, J = 8.6 Hz, 1 H), 4.44-4. 39 (m, 1 H), 3.21 (dd, J ₁ = 5.0 Hz, J ₂ = 14.2 Hz, 1 H), 3.07 (dd, J ₁ = 6.9 Hz, J ₂ = 14.2 Hz, 1 H), 1. 92 (s, 3 H), 1.52-1. 46 (m, 2 H), 1.43-1. 37 (m, 2 H) ), 0.89 (t, J = 7.2 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 168.99, 159.29, 147.07, 136.12, 129.12, 128.30, 127.21, 126.37, 125.61, 121.74, 48.66, 42.03, 36.40 , 23.11, 18.97, 13.50; HRMS (ESI-TOF) calcd _{C 16 H 21 N 2 O [} M + H] +: 257.1648; Found: 257.1647.
Diffusion from CHCl ₃ and hexane was used to obtain crystals of L13 suitable for X-ray analysis.

(S) -N- (4-Methyl-1- (quinolin-2-yl) pentan-2-yl) acetamide (L14)
White solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, J = 8.4 Hz, 1 H), 8.05 (d, J = 8.5 Hz, 1 H), 7.80 (dd, J ₁ = 1.4 Hz, J ₂ = 8.2 Hz , 1H), 7.72-7.68 (m, 1H), 7.54-7.50 (m, 1H), 7.40 (d, J = 8.4 Hz, 1 H), 6.87 (d, J = 9.2 Hz, 1 H), 6.34 (br s , 1H), 4.54-4.46 (m, 1H), 3.20 (dd, J 1 = 4.8 Hz, J 2 = 13.8 Hz, 1H), 3.03 (dd, J 1 = 8.6 Hz, J 2 = 13.8 Hz, 1H) , 2.12 (s, 3 H), 1.72-1. 65 (m, 1 H), 1.50-1. 43 (m, 1 H), 1.37-1. 30 (m, 1 H), 0.93 (d, J = 6.6 Hz, 6 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.87, 159.63, 146.52, 137.90, 127.74, 127.49, 126.29, 122.16, 47.71, 44.57, 42.95, 25.02, 23.06, 22.89, 22.36; HRMS (ESI-TOF) C ₁₇ Calculated value for H ₂₃ N ₂ O [M + H] ⁺ : 271.1805; found: 271.1796.
Absolute stereochemistry was assigned by similarity to compound L13.

(S) -N- (1-phenyl-3- (quinolin-2-yl) propan-2-yl) acetamide (L15)
White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.09 (d, J = 8.4 Hz, 1 H), 8.03-8.01 (m, 1 H), 7.81 (dd, J ₁ = 1.4 Hz, J ₂ = 8.2 Hz, 1 H) , 7.73-7.70 (m, 1H), 7.54-7.51 (m, 1H), 7.30 (dd, J 1 = 6.8 Hz, J 2 = 8.2 Hz, 2H), 7.25-7.20 (m, 4H), 7.00 (d , J = 8.1 Hz, 1 H), 4.64 (m, 1 H), 3.17 (dd, J ₁ = 4.9 Hz, J ₂ = 14.5 Hz, 1 H), 3.05 (dd, J ₁ = 5.5 Hz, J ₂ = 13.6 Hz , 1H), 2.98 (dd, J 1 = 7.2 Hz, J 2 = 14.5 Hz, 1H), 2.76 (dd, J 1 = 8.3 Hz, J 2 = 13.6 Hz, 1H), 1.91 (s, 3H); 13 C NMR (150 MHz, CDCl ₃ ) δ 169.48, 159.56, 147.18, 136.61, 129.62, 129.70, 128.46, 127.66, 126.81, 126.44, 126.14, 122.29, 50.64, 40.54, 40.14, 23.53; HRMS (ESI-MS) TOF) calcd _{C 20 H 21 N 2 O [} M + H] +: 305.1648; Found: 305.1645.
Absolute stereochemistry was assigned by similarity to compound L13.

(R) -N- (3-Methyl-1- (quinolin-2-yl) butan-2-yl) acetamide (L16)
White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.11 (d, J = 8.4 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 7.81-7.80 (m, 1 H), 7.72-7.70 (m, 1H), 7.54-7.51 (m, 1H), 7.37 (d, J = 8.4 Hz, 1 H), 6.49 (d, J = 9.2 Hz, 1 H), 4.44-4. 39 (m, 1 H), 4.27-4.22 (m , 1H), 3.21 (dd, J 1 = 4.2 Hz, J 2 = 14.2 Hz, 1H), 3.03 (dd, J 1 = 9.1 Hz, J 2 = 14.2 Hz, 1H), 1.88-1.84 (m, 4H) , 0.99 (d, J = 6.6 Hz, 3 H), 0.98 (d, J = 6.6 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.06, 159.93, 137.01, 129.78, 128.19, 127.75, 126.86, HRMS (ESI-TOF) Calcd for C ₁₆ H ₂₁ N ₂ O [M + H] ⁺ : 257.1648; found: 257.1650. 126.19, 121.93, 54.67, 40.02, 31.28, 19.11, 18.58;
Absolute stereochemistry was assigned by similarity to compound L13.

(R) -N- (1-phenyl-2- (quinolin-2-yl) ethyl) acetamide (L17)
White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.05 (dd, J ₁ = 1.0 Hz, J ₂ = 8.4 Hz, 1 H), 8.01 (dd, J ₁ = 0.8 Hz, J ₂ = 8.4 Hz, 1 H), 7.78 _{(dd, J 1 = 1.3 Hz} , J 2 = 8.0 Hz, 1H), 7.74-7.71 (m, 1H), 7.54-7.51 (m, 2H), 7.26-7.22 (m, 4H), 7.20-7.17 (m , 1H), 7.11 (d, J = 8.4 Hz, 1H), 5.48 (dt, J ₁ = 4.9 Hz, J ₂ = 7.5 Hz, 1 H), 3.49 (dd, J ₁ = 4.9 Hz, J ₂ = 14.0 Hz , ₁ H), _3. 35 (dd, J ₁ = 7.6 Hz, J ₂ = 14.0 Hz, 1 H), 1. 97 (s, 3 H). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 168.89, 158.46, 147.00, 141.35, 136.18 , 129.24, 128.25, 127.96, 127.25, 126.66, 125.81, 125.77, 121.77, 52.69, 43.83, 22.96; HRMS (ESI-TOF) C ₁₉ H ₁₉ N ₂ O calculated value [M + H] ⁺ : 291.1492; Found: 291.1491.
Absolute stereochemistry was assigned by similarity to compound L21.

(R) -N- (1- (2-fluorophenyl) -2- (quinolin-2-yl) ethyl) acetamide (L18)
White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.03 (d, J = 8.5 Hz, 1 H), 7.95 (d, J = 8.4 Hz, 1 H), 7.75-7.67 (m, 3 H), 7.49-7.46 (m, 1H), 7.14 -7.06 (m, 3H), 7.01-6.97 (m, 1H), 6.90 (dt, J 1 = 1.2 Hz, J 2 = 7.5 Hz, 1H), 5.72 (dd, J 1 = 5.1 Hz, J ₂ = 7.6 Hz, ₁ H), 3. 45 (dd, J ₁ = 5.2 Hz, J ₂ = 14.0 Hz, 1 H), 3. 38 (dd, J ₁ = 7.6 Hz, J ₂ = 14.0 Hz, 1 H), 1. 95 (s , 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.24, 160.11 (d, J _FC = 244.5 Hz), 158.51, 147. 27, 136. 46, 129.48, 128. 58 (d, J _FC = 4.5 Hz), 128.53, 128. 50 , 127.81 (d, J _FC = 4.5 Hz), 127.51, 126.69, 126.03, 123.82 (d, J _FC = 3 Hz), 121.87, 115.32 (d, J _FC = 22.5 Hz), 48.49 (d, J _FC = 1.5) Hz), 42.85 (d, J _FC = 1.5 Hz), 23.08; HRMS (ESI-TOF) Calcd for C ₁₉ H ₁₈ FN ₂ O [M + H] ⁺ : 309.1398; found: 309.1398
Absolute stereochemistry was assigned by similarity to compound L21.

(R) -N- (1- (2-chlorophenyl) -2- (quinolin-2-yl) ethyl) acetamide (L19)
White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.07-8.05 (m, 1 H), 7. 98 (d, J = 8.3 Hz, 1 H), 7. 87 (d, J = 6.9 Hz, 1 H), 7. 77 (dd, J _{1 = 1.4 Hz, J 2 = 8.2} Hz, 1H), 7.73-7.70 (m, 1H), 7.53-7.50 (m, 1H), 7.34 (dd, J 1 = 1.2 Hz, J 2 = 7.9 Hz, 1H), 7.11-7.07 (m, 2H), 7.05-7.00 (m, 2H), 5.75 (dt, J 1 = 4.5 Hz, J 2 = 7.3 Hz, 1H), 3.49 (dd, J 1 = 4.5 Hz, J 2 = 14.0 Hz, 1 H), 3.33 (dd, J ₁ = 7.7 Hz, J ₂ = 14.0 Hz, 1 H), 1. 97 (s, 3 H). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.25, 158.68, 147.27, 138.98 , 136.65, 132.21, 129.66, 129.64, 128.14, 127.64, 127.09, 126.62, 126.66, 126.18, 122.08, 50.97, 41.94, 23.17; HRMS (ESI-TOF) C ₁₉ H ₁₈ ClN ₂ O calculated value [M + H] ⁺ : 325.1102; Found: 325.1105.
Absolute stereochemistry was assigned by similarity to compound L21.

(R) -N- (2- (quinolin-2-yl) -1- (o-tolyl) ethyl) acetamide (L20)
White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.07 (d, J = 8.5 Hz, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.78 (dd, J ₁ = 1.4 Hz, J ₂ = 8.1 Hz , 1H), 7.74-7.71 (m, 1H), 7.54-7.51 (m, 1H), 7.31 (br s, 1H), 7.14-7.08 (m, 3H), 7.07-7.02 (m, 2H), 5.65 (5, 6) dt, J ₁ = 5.2 Hz, J ₂ = 7.6 Hz, 1 H, _3. 40 (dd, J ₁ = 5.2 Hz, J ₁ = 13. 8 Hz, ₁ H), _3. 29 (dd, J ₁ = 7.9 Hz, J ₂ = 13.8 Hz, 1 H), 2. 49 (s, 3 H), 1. 92 (s, 3 H). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.12, 158.84, 147.39, 136.96, 136.63, 135.05, 130.53, 129.68, 128.62, 127.67, Calculated value for C ₂₀ H ₂₁ N ₂ O [M + H] ⁺ : 305.1648; found: 305.1647. 126.99, 126.86, 126.19, 126.01, 125.25, 122.07, 49.83, 43.42, 23.23, 19.27.
Absolute stereochemistry was assigned by similarity to compound L21.

L21 X-ray

(R) -N- (2- (quinolin-2-yl) -1- (2- (trifluoromethyl) phenyl) ethyl) acetamide (L21)
White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.09-8.02 (m, 2 H), 7. 94 (d, J = 5.8 Hz, 1 H), 7. 79 (dd, J ₁ = 1.4 Hz, J ₂ = 8.0 Hz, 1 H) , 7.74-7.71 (m, 1H), 7.65 (dd, J 1 = 1.4 Hz, J 2 = 7.8 Hz, 1H), 7.55-7.52 (m, 1H), 7.37-7.27 (m, 3H), 7.16 (d , J = 8.4 Hz, 1 H), 5.69 (dq, J ₁ = 4.4 Hz, J ₂ = 9.4 Hz, 1 H), _3. 45 (dd, J ₁ = 4.1 Hz, J ₂ = 14.0 Hz, 1 H), _3. 19 (dd , J ₁ = 8.9 Hz, J ₂ = 14.0 Hz, 1 H), 1.90 (s, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.40, 158.48, 147.25, 141.66 (q, J _FC = 1.5 Hz) , 136.98, 131.86, 129.76, 128.46 , 127.70, 127.11, 127.05 (q, J FC = 30 Hz), 127.00, 126.91, 126.30, 126.02 (q, J FC = 6.0 Hz), 124.54 (q, J FC = 273 Hz ), 122.01, 50.34 (q, J FC = 1.5 Hz), 44.44, 22.97; HRMS (ESI-TOF) calcd _{C 20 H 18 F 3 N 2} O [M + H] +: 359.1365; Found: 359.1366 .
Diffusion from CHCl ₃ and hexane was used to obtain crystals of L21 suitable for X-ray analysis.

(R) -N- (2- (quinolin-2-yl) -1- (m-tolyl) ethyl) acetamide (L22)
White solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (d, J = 8.4 Hz, 1 H), 8.03 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 7.72 (t , J = 7.7 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 1 H), 7. 47 (d, J = 7.7 Hz, 1 H), 7. 16 (d, J = 8.3 Hz, 1 H), 7.12 (d, J = 7.5 Hz, 1 H), 7.09 (s, 1 H), 7.01 (t, J = 8.6 Hz, 2 H), 5. 44 (q, J = 7.5 Hz, 1 H), _3. 47 (dd, J ₁ = 4.9 Hz, J ₂ = 13.9 Hz, 1 H), _3. 35 (dd, J ₁ = 8.0 Hz, J ₂ = 13.9 Hz, 1 H), 2. 28 (s, 3 H), 1. 93 (s, 3 H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.29, 158.87, 147.14, 141.72, 137.96, 126.73, 128.27, 127.85, 127.11, 126.13, 126.23, 123.18, 122.13, 54.13, 44.30, 23.31, 21.39. HRMS (ESI-TOF) C ₂₀ H ₂₁ N ₂ O calculated value [M + H] ⁺ : 305.1649; found: 305.1647.
Absolute stereochemistry was assigned by similarity to compound L21.

(R) -N- (1- (3- (tert-butyl) phenyl) -2- (quinolin-2-yl) ethyl) acetamide (L23)
Yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (d, J = 8.5 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 7.72-7.67 (m, 1H), 7.52-7.47 ( m, 2H), 7.23-7.15 (m, 3H), 7.09 (dd, J 1 = 7.7 Hz, J 2 = 14.6 Hz, 2H), 5.51 (dt, J 1 = _{4.8 Hz, J 2 = 7.7 Hz} , 1H), 3.47 (dd, J 1 = 5.1 Hz, J 2 = 13.9 Hz, 1H), 3.35 (dd, J 1 = 7.6 Hz, J 2 = 13.8 Hz, 1H), 1.93 (s, 3 H), 1. ¹⁹ (s, 9 H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.17, 158.97, 150.99, 147.38, 141.27, 136.34, 129.49, 128.57, 127.98, 127.52, 126.72, 126.92, 123.99 , 123.36, 123.28, 122.10, 53.28 , 44.55, 34.47, 31.14, 23.26.HRMS (ESI-TOF) calcd _{C 23 H 27 N 2 O [} M + H] +: 347.2118; Found: 347.2119.
Absolute stereochemistry was assigned by similarity to compound L21.

(R) -N- (1- (4-methoxyphenyl) -2- (quinolin-2-yl) ethyl) acetamide (L24)
Yellow oil. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.04 (d, J = 8.4 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 1 H), 7.78 (dd, J ₁ = 1.4 Hz, J ₂ = 8.1 Hz , 1H), 7.73-7.70 (m, 1H), 7.53-7.50 (m, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.16-7.14 (m, 2H), 7.13 (d, J = 8.4) Hz, 1H), 6.79 -6.76 ( m, 2H), 5.44 (dt, J 1 = 5.1 Hz, J 2 = 7.5 Hz, 1H), 3.74 (s, 3H), 3.46 (dd, J 1 = 5.1 Hz, J ₂ = 13.9 Hz, 1 H), 3.34 (dd, J ₁ = 7.6 Hz, J ₂ = 14.0 Hz, 1 H), 1.94 (s, 3 H). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.25, 159.00, 158.55, 147.41, 136.57, 133.95, 129.62, 127.66, 127.42, 126.15, 122.20, 113.76, 55.17, 54.34, 23.37. HRMS (ESI-TOF) C ₂₀ H ₂₁ N ₂ O ₂ calculated values [ M + H] ⁺ : 321.1598; Found: 321.1593.
Absolute stereochemistry was assigned by similarity to compound L21.

(R) -N- (2- (quinolin-2-yl) -1- (4- (trifluoromethyl) phenyl) ethyl) acetamide (L25)
¹ H NMR (600 MHz, CDCl ₃ ) δ 8.05 (d, J = 8.6 Hz, 1 H), 8.03 (d, J = 8.4 Hz, 1 H), 7.95 (d, J = 6.9 Hz, 1 H), 7.80 (dd , J ₁ = 1.3 Hz, J ₂ = 8.1 Hz, 1 H), 7. 75 (ddd, J ₁ = 1.4 Hz, J ₂ = 6.9 Hz, J ₃ = 8.4 Hz, 1 H), 7.55 (ddd, J ₁ = 1.2 Hz , J ₂ = 6.9 Hz, J ₃ = 8.1 Hz, 1 H), 7. 49 (d, J = 7.9 Hz, 2 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.06 (d, J = 8.4 Hz, 1 H) ), 5.49 (dt, J ₁ = 4.7 Hz, J ₂ = 7.0 Hz, 1 H), 3.51 (dd, J ₁ = 4.8 Hz, J ₂ = 14.2 Hz, 1 H), 3.33 (dd, J ₁ = 7.2 Hz, J ₂ = 14.2 Hz, 1 H), 2.02 (s, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) 169.55, 158.28, 147.34, 145.98 (q, J _FC = 1.4 Hz), 136.96, 129.94, 129.28 (q , J _FC = 32.3 Hz), 128.62, 127.76, 126.89, 126.57, 126.46, 125.37 (q, J _FC = 3.8 Hz), 124.07 (q, J _FC = 272.0 Hz), 122.19, 52.96, 43.56, 23.35; ¹⁹ F NMR (375 MHz, CDCl ₃ ) δ -62.7; HRMS (ESI-TOF) calculated for C ₂₀ H ₁₈ F ₃ N ₂ O [M + H] ⁺ 359.1366, found 359.1364
Absolute stereochemistry was assigned by similarity to compound L21.

(R) -N- (1- (2,6-difluorophenyl) -2- (quinolin-2-yl) ethyl) acetamide (L26)
White oil. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.06 (d, J = 8.4 Hz, 1 H), 8.01 (dt, J ₁ = 0.9 Hz, J ₂ = 8.4 Hz, 1 H), 7.77 (dd, J ₁ = 1.4 Hz, J ₂ = 8.2 Hz, 1 H), 7. 70-7. 67 (m, 1 H), 7.5 1-7. 49 (m, 1 H), 7. 29 (d, J = 8.4 Hz, 1 H), 7. 18-7. 13 (m, 1 H), 6.85-6.80 (m, 3H), 5.96 (dt, J 1 = 6.0 Hz, J 2 = 8.6 Hz, 1H), 3.51 (dd, J 1 = 8.8 Hz, J 2 = 13.7 Hz, 1H), 3.42 (dd , J ₁ = 6.0 Hz, J ₂ = 13.7 Hz, 1 H), 1. 88 (s, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.28, 160.87 (dd, J _FC1 = 246 Hz, J _{FC 2} = 9 Hz), 157.92, 147.63, 136.67 , 129.53, 128.97 (t, J FC = 10.5 Hz), 128.79, 127.57, 126.89, 126.15, 121.42, 117.33 (t, J FC = 16.5 Hz), 111.63 (dd, J FC1 = 4.5 Hz, J _FC2 = 21.0 Hz), 44.70 (t, J _FC = 1.5 Hz), 43.45, 23.12; HRMS (ESI-TOF) C ₁₉ H ₁₇ F ₂ N ₂ O calculated values [M + H] ⁺ : 667.4622; Found: 667.4625.
Absolute stereochemistry was assigned by similarity to compound L21.

(R) -N- (1- (2,6-dichlorophenyl) -2- (quinolin-2-yl) ethyl) acetamide (L27)
White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.11 (dd, J ₁ = 0.8 Hz, J ₂ = 8.4 Hz, 1 H), 8.06 (dq, J ₁ = 0.9 Hz, J ₂ = 8.5 Hz, 1 H), 7.80 _{(dd, J 1 = 1.4 Hz} , J 2 = 8.1 Hz, 1H), 7.72-7.69 (m, 1H), 7.54-7.51 (m, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.29 ( d, J = 8.0 Hz, 2 H), 7.12 (t, J = 8.0 Hz, 1 H), 7.08 (d, J = 8.1 Hz, 1 H), 6.31-6.27 (m, 1 H), 3.68 (dd, J ₁ = 10.6 Hz, J ₂ = 13.7 Hz, 1 H), 3.41 (dd, J ₁ = 5.2 Hz, J ₂ = 13.7 Hz, 1 H), 1. 84 (s, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.36 HRMS (ESI-TOF) C ₁₉ H ₁₇ N ₂ O calculated values [M + H], 158.09, 147.40, 137.03, 135.92, 129.80, 128.50, 127.60, 126.95, 126.23, 121.40, 51.01, 41.25, 22.82; ⁺ : 359.0712; Found: 359.0707.
Absolute stereochemistry was assigned by similarity to compound L21.

(R) -N- (1- (2,6-dimethylphenyl) -2- (quinolin-2-yl) ethyl) acetamide (L28)
White oil. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.12 (d, J = 8.4 Hz, 1 H), 8.09 (d, J = 8.5 Hz, 1 H), 7.83 (d, J = 8.1 Hz, 1 H), 7.76-7.73 (m, 1 H), 7.57-7.54 (m, 1 H), 7.32 (d, J = 8.3 Hz, 1 H), 7.07 (dd, J ₁ = 6.5 Hz, J ₂ = 8.3 Hz, 1 H), 7.01 (d, J = 7.4 Hz, 2 H), 6.81 (d, J = 6.7 Hz, 1 H), 5. 80 (dt, J ₁ = 6.0 Hz, J ₂ = 10.9 Hz, 1 H), 3.55 (dd, J ₁ = 10.5 Hz, J ₂ = 13.8 Hz, 1 H), 3.36-3.32 (m, 1 H), 2.53 (s, 6 H), 1.86 (s, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.32, 159.01, 147.55, 137.60, 136.99, 129.70, 128.64, 127.66, 127.04, 126.91, 126.21, 121.46, 51.01, 42.28, 22.96, 21.14; C 22 H 25 N 2 calculated O [M + H] +: 333.1961; Found: 333.1966.
Absolute stereochemistry was assigned by similarity to compound L21.

(R) -N- (1- (2,6-dimethoxyphenyl) -2- (quinolin-2-yl) ethyl) acetamide (L29)
White solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03-7.97 (m, 2 H), 7.74 (dd, J ₁ = 1.5 Hz, J ₂ = 8.0 Hz, 1 H), 7.65-7.61 (m, 1 H), 7.47- 7.41 (m, 2H), 7.15 (t, J = 8.4 Hz, 1 H), 7.05 (d, J = 9.9 Hz, 1 H), 6.50 (d, J = 8.4 Hz, 2 H), 6.34-6.28 (m, 1 H) ), 3.73 (s, 6 H), _3. 47 (dd, J ₁ = 8.7 Hz, J ₂ = 13.2 Hz, 1 H), 3.32 (dd, J ₁ = 6.0 Hz, J ₂ = 13.3 Hz, 1 H), 1.82 (s , 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.72, 159.69, 157.85, 147.58, 135.95, 128.75, 128.75, 128.53, 126.82, 125.60, 121.95, 117.04, 104.18, 55.74, 44.78, 44.31, 23.50 ; HRMS (ESI-TOF) calcd _{C 21 H 23 N 2 O 3} [M + H] +: 351.1703; Found: 321.1693.
Absolute stereochemistry was assigned by similarity to compound L21.

(R) -N- (1- (3,5-Dimethylphenyl) -2- (quinolin-2-yl) ethyl) acetamide (L30)
White solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (t, J = 9.4 Hz, 2 H), 7.78 (d, J = 8.1 Hz, 1 H), 7.71 (t, J = 7.7 Hz, 1 H), 7.51 (t , J = 7.5 Hz, 1 H), 7. 38-7. 25 (m, 1 H), 7. 18 (d, J = 8.3 Hz, 1 H), 6. 88 (s, 2 H), 6. 83 (s, 1 H), 5. 39 (dd, J _{1 = 5.0 Hz, J 2 = 8.0} Hz, 1H), 3.44 (dd, J 1 = 4.9 Hz, J 2 = 13.8 Hz, 1H), 3.32 (dd, J 1 = 8.3 Hz, J 2 = 13.9 Hz, 1H) , 2.24 (s, 6 H), 1. 92 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.27, 158.96, 147.42, 141.75, 137.48, 129.55, 128.80, 128.62, 127.61, 126.81, 126.08, 124.08, 122.06, 53.16, 44.59, 23.31, 21.27; HRMS calcd for _{(ESI-TOF) C 21 H} 23 N 2 O [M + H] +: 319.1805; Found: .319.1807.
Absolute stereochemistry was assigned by similarity to compound L21.

(R) -N- (1- (3,5-bis (trifluoromethyl) phenyl) -2- (quinolin-2-yl) ethyl) acetamide (L31)
White solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09-8.03 (m, 3H), 7.82-7. 73 (m, 2H), 7.70-7.67 (m, 3H), 7.57-7.53 (m, 1H), 7.07 (d , J = 8.4 Hz, 1 H), 5.52 (dt, J ₁ = 4.6 Hz, J ₂ = 7.0 Hz, 1 H), 3.54-3.49 (m, 1 H), 3.35-3.29 (m, 1 H), 2.03 (s, 3H). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.84, 157.54, 147.37, 144.86, 137.17, 131.55 (q, J _FC = 33 Hz), 130.12, 128.56, 127.75, 126.90, 126.78 (q, J _FC = 36 Hz), 123.20 (q, J FC = 272 Hz), 121.96, 121.13 (q, J FC = 3 Hz), 109.97, 52.78, 43.35, 23.29; HRMS (ESI-TOF) C 21 H 17 F 6 N 2 Calculated value for O [M + H] ⁺ : 427.1240; found: 427.1233.
Absolute stereochemistry was assigned by similarity to compound L21.

(R) -N- (1- (3,5-di-tert-butylphenyl) -2- (quinolin-2-yl) ethyl) acetamide (L32)
White foam, [α] _D ²⁰ = -93.2 (c = 0.97, CHCl ₃ ). ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.06-8.04 (m, 1 H), 8.02-8.00 (m, 1 H), 7.77 (dd, J ₁ = 8.2 Hz, J ₂ = 1.4 Hz, 1 H), 7.73- 7.70 (m, 1 H), 7.52-7. 50 (m, 1 H), 7. 25 (t, J = 1.8 Hz, 1 H), 7. 17 (d, J = 8.4 Hz, 1 H), 7.08 (d, J = 1.8 Hz, 2 H ), 5.53 (dd, J ₁ = 4.9 Hz, J ₂ = 8.1 Hz, 1 H), _3. 49 (dd, J ₁ = 5.0 Hz, J ₂ = 13.9 Hz, 1 H), _3. 37 (dd, J ₁ = 8.2 Hz, J ₂ = 13.9 Hz, 1 H), 1. 92 (s, 3 H), 1.23 (s, 18 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.12, 159.22, 150.69, 147.46, 140.72, 136.44, 129.56, 128.61, 127.61, 126.86, 126.08, 122.15, 121.23, 120.66, 53.53, 34.77, 31.38, 23.41. HRMS (ESI-TOF) C ₂₇ H ₃₅ N ₂ O calculated value [M + H] ⁺ : 403.2744; actual value: 403.2747.
Absolute stereochemistry was assigned by similarity to compound L32.

(R) -N- (1-([1,1 ′: 3 ′, 1 ′ ′-terphenyl] -5′-yl) -2- (quinolin-2-yl) ethyl) acetamide (L33)
White foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (d, J = 8.5 Hz, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.82 (d, J = 8.1 Hz, 1 H), 7.78-7.73 (m, 2H), 7.61 (d, J = 1.9 Hz, 1 H), 7.57 (t, J = 7.5 Hz, 1 H), 7.48-7.46 (m, 3 H), 7.41-7.31 (m, 7 H), 7.18 (7 d, J = 8.4 Hz, 1 H), 5.64-5.59 (m, 1 H), 3.59 (dd, J ₁ = 4.7 Hz, J ₂ = 14.0 Hz, 1 H), 3.43 (dd, J ₁ = 7.6 Hz, J ₂ = 14.0 Hz, 1 H), 1.99 (s, 3 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 169.43, 158.85, 147.37, 142.88, 141.76, 140.94, 126.72, 128.61, 127.62, 127.29, 127.13, 126.86 , 126.23, 124.96, 124.25, 122.30 , 53.28, 44.30, 23.31; HRMS calcd for _{(ESI-TOF) C 31 H} 27 N 2 O [M + H] +: 443.2118; Found: 443.2127.
Absolute stereochemistry was assigned by similarity to compound L32.

General Procedure for the Synthesis of L34 to L39, L40a, L41

Synthesis of tert-butanesulfinylamine L35-1

N-Butyllithium (2.5 M in hexane, 26 mmol, 16.25 mL, 1.3 eq) was added dropwise to a solution of 2-propylquinoline (4.45 g, 26 mmol, 1.3 eq) in anhydrous THF (30 mL) at 0 ° C. The resulting solution was slowly cooled to room temperature and stirred for 3 hours. The mixture was then cooled to −78 ° C. and to this was added dropwise tert-butanesulfinylimine (6.44 g, 20 mmol, 1 equivalent) in anhydrous THF (30 mL). The resulting mixture was warmed to 0 ° C. for 2 hours and then treated with saturated aqueous NH ₄ Cl. The product was extracted with dichloromethane. The combined extracts were washed with water, dried over anhydrous MgSO ₄ and concentrated in vacuo. By flash chromatography (eluent: ethyl acetate / hexane = 1/10 → 1/2), L35-1b (least polar compound, 3.52 g, 36% yield), L35-1c and L35-1d (column separation) Three fractions were obtained which contained a mixture of two diastereomers which could not be obtained, 1.60 g, 16% yield) and L 35-1a (most polar compound, 2.30 g, 23% yield).

1-tert-Butyl-N-((1R, 2S) -1- (3,5-di-tert-butylphenyl) -2- (quinolin-2-yl) butyl) -1- (λ ¹ -oxydanyl) -λ ³ -sulfanamine (L 35-1 b)
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (dd, J ₁ = 1.0 Hz, J ₂ = 8.4 Hz, 1 H), 7.88 (dd, J ₁ = 0.8 Hz, J ₂ = 8.5 Hz, 1 H), 7.73 -7.67 (m, 2H), 7.49-7.45 (m, 1H), 7.13 (t, J = 1.8 Hz, 1 H), 6.92 (d, J = 1.8 Hz, 2 H), 6.84 (d, J = 8.4 Hz, 1H), 5.69 (d, J = 8.1 Hz, 1H), 4.77 (dd, J 1 = 6.1 Hz, J 2 = 8.1 Hz, 1H), 3.19-3.13 (m, 1H), 2.04-1.96 (m, 1H ), 1.95-1.85 (m, 1 H), 1.14 (s, 18 H), 1.10 (s, 9 H), 0.82 (t, J = 7.4 Hz, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 162.86, HRMS (ESI-TOF) C ₃₁ H ₄₅ 150.00, 147.39, 141.09, 135.74, 128.79, 127.34, 126.88, 125.91, 122.62, 121.52, 120.42, 56.89, 56.32, 34.57, 31.26, 26.29, 22.56, 12.13; Calculated value for N ₂ OS [M + H] ⁺ : 493.3247; found: 493.3245.
Absolute stereochemistry was assigned by similarity to compound L40b.

1-tert-Butyl-N-((1S, 2S) -1- (3,5-di-tert-butylphenyl) -2- (quinolin-2-yl) butyl) -1- (λ ¹ -oxydanyl) -λ ³ -sulfanamine (L 35-1a)
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07-7.99 (m, 1 H), 8.00 (dd, J ₁ = 0.8 Hz, J ₂ = 8.5 Hz, 1 H), 7.79-7.76 (m, 1 H), 7.72- 7.68 (m, 1H), 7.53-7.48 (m, 1H), 7.27 (dd, J 1 = 1.8 Hz, J 2 = 3.6 Hz, 1H), 7.03-7.01 (m, 3H), 6.15 (d, J = 1.3 Hz, 1 H), 4.87-4. 85 (m, 1 H), 3.18 (dt, J ₁ = 3.9 Hz, J ₂ = 11.0 Hz, 1 H), 2.03 (dt, J ₁ = 6.8 Hz, J ₂ = 11.0 Hz, 1H), 1.86-1.79 (m, 1H), 1.32 (s, 9H), 1.26 (s, 18H), 0.71 (t, J = 7.3 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 162.46 , 149.86, 147.40, 138.97, 136.06, 129.88, 127.52, 127.09, 126.82, 122.78, 120.99, 60.84, 55.94, 35.90, 31.41, 23.03, 21.47, 12.24; HRMS (ESI-TOF) C ₃₁ H Calculated value for ₄₅ N ₂ OS [M + H] ⁺ : 493.3247; found: 493.3249.
Absolute stereochemistry was assigned by similarity to compound L35.

Synthesis of Ligands L40a and L40b
About L40b:
To a solution of tert-butanesulfinylamine L35b (1.40 g, 2.84 mmol) in MeOH (10 mL) at room temperature was added HCl solution (4 N in dioxane, 11.4 mmol, 2.84 mL). The mixture was stirred for 6 hours and then the solvent was removed by reduced pressure. The crude oil was treated with saturated aqueous Na ₂ CO ₃ and extracted with dichloromethane. The combined extracts were washed with water, dried over anhydrous MgSO ₄ and concentrated in vacuo. Flash chromatography (eluent: dichloromethane / methanol = 20/1) gave amine L40b (990 mg, 90% yield) as a pale yellow oil.

(1R, 2S) -1- (3,5-di-tert-butylphenyl) -2- (quinolin-2-yl) butane-1-amine (L40b):
¹ H NMR (600 MHz, CDCl ₃ ) δ 8.13 (d, J = 8.5 Hz, 1 H), 8.07 (d, J = 8.5 Hz, 1 H), 7.80 (d, J = 8.1 Hz, 1 H), 7.71 (t , J = 7.7 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.34-7.29 (m, 2 H), 7.21 (s, 2 H), 4.37 (d, J = 9.0 Hz, 1 H), 3.10 _{(dt, J 1 = 4.0 Hz} , J 2 = 9.9 Hz, 1H), 1.78-1.73 (m, 1H), 1.59-1.54 (m, 1H), 1.32 (s, 18H), 0.65 (t, J = 7.4 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 164.03, 150.61, 148.03, 144.91, 129.12, 129.15, 127.52, 125.78, 122.01, 121.47, 120.95, 61.15, 58.37, 34.84, 31.51 HRMS (ESI-TOF) calculated for C ₂₇ H ₃₇ N ₂ O [M + H] ⁺ : 389.2951; found: 389.2949.

Preparation of HCl salt of amine L40b
To a solution of amine L40b (20 mg, 0.05 mmol) in a 5 mL vial was added a solution of HCl in dioxane (4 N, 0.1 mL, 0.4 mmol). The mixture was stirred at room temperature for 30 minutes. The solvent was removed under vacuum and a small amount of CHCl ₃ was added to the vial to dissolve the resulting salt. Solvent evaporation was used to obtain suitable crystals suitable for X-ray analysis.
Synthesis of L40a To a solution of tert-butanesulfinylamine L35-1b (500 mg, 1 mmol) in MeOH (10 mL) at room temperature was added HCl solution (4 N in dioxane, 4 mmol, 1 mL). The mixture was stirred for 6 hours and then the solvent was removed by reduced pressure. To the resulting foam was added CH ₂ Cl ₂ (10 mL) and Et ₃ N (405 mg, 4 mmol, 0.57 mL) at room temperature followed by acetic anhydride (405 mg, 5 mmol, 0.38 mL). The mixture was stirred overnight (about 18 hours) and then treated with saturated aqueous Na ₂ CO ₃ solution. The product was extracted with dichloromethane. The combined extracts were washed with water, dried over anhydrous MgSO ₄ and concentrated in vacuo. Flash chromatography (eluent: ethyl acetate / hexane = 1/3) gave ligand L40a (323 mg, 75% yield) as a white solid, [α] _D ²⁰ = 243.60 (c = 0.74, CHCl ₃ ) The

N-((1R, 2S) -1- (3,5-di-tert-butylphenyl) -2- (quinolin-2-yl) butyl) acetamide (L40a)
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41 (d, J = 9.0 Hz, 1 H), 8.13-8.11 (m, 1 H), 8.04 (d, J = 8.5 Hz, 1 H), 7.79-7.72 (m, 2H), 7.54-7.50 (m, 1H), 7.20 (t, J = 1.8 Hz, 1 H), 7.16 (d, J = 8.5 Hz, 1 H), 6.99 (d, J = 1.8 Hz, 2 H), 5. 39 ( dd, J ₁ = 7.5 Hz, J ₂ = 9.0 Hz, 1 H), 3. 26-3. 20 (m, 1 H), 1.92-1. 75 (m, 5 H), 1. 19 (s, 18 H), 0.77 (t, J = 7.4 Hz , 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.26, 163.36, 150.16, 146.88, 140.91, 129.59, 128.20, 127.55, 126.97, 126.12, 122.36, 120.69, 120.55, 56.86, 54.94, 34.52 , 26.47, 23.34, 12.18; HRMS calcd for _{(ESI-TOF) C 29 H} 39 N 2 O [M + H] +: 431.3057; Found: 431.3057.
Absolute stereochemistry was assigned by similarity to compound L40b.

Synthesis of L35 To a solution of tert-butanesulfinylamine L35-1a (860 mg, 1.75 mmol) in MeOH (10 mL) at room temperature was added HCl solution (4 N in dioxane, 7 mmol, 1.75 mL). The mixture was stirred for 6 hours and then the solvent was removed by reduced pressure. To the resulting foam was added CH ₂ Cl ₂ (10 mL) and Et ₃ N (710 mg, 7 mmol, 1 mL) at room temperature followed by acetic anhydride (710 mg, 7 mmol, 0.67 mL). The mixture was stirred overnight (about 18 hours) and then treated with saturated aqueous Na ₂ CO ₃ solution. The product was extracted with dichloromethane. The combined extracts were washed with water, dried over anhydrous MgSO ₄ and concentrated in vacuo. Ligand L35 (620 mg, 80% yield) as white foam, [α] _D ²⁰ = -207.8 (c = 0.96, CHCl ₃ ) by flash chromatography (eluent: ethyl acetate / hexane = 1: 2) Obtained. A diffusion method from CHCl ₃ and hexane was used to obtain crystals suitable for X-ray analysis of the HCl salt of L35.

N-((1S, 2S) -1- (3,5-di-tert-butylphenyl) -2- (quinolin-2-yl) butyl) acetamide (L35)
¹ H NMR (600 MHz, CDCl ₃ ) δ 8.06 (dd, J ₁ = 1.0 Hz, J ₂ = 8.4 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.72-7.68 (m, 2 H) , 7.50-7.47 (m, 1 H), 7.12-7.09 (m, 2 H), 6. 80 (d, J = 8.5 Hz, 2 H), 6. 68 (d, J = 1.8 Hz, ₁ H), 5. 38 (dd, J ₁ = _{6.5 Hz, J 2 = 8.2 Hz} , 1H), 3.35-3.31 (m, 1H), 2.04 (s, 3H), 1.93 (t, J = 7.5 Hz, 2H), 1.09 (s, 18H), 0.90 (t , J = 7.4 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.03, 161.86, 149.85, 147.61, 135.69, 129.33, 128.85, 126.95, 126.90, 126.03, 121.50, 121.03, 120.80, 57.35, 54.74, 34.52, 31.21, 23.90, 23.63, 12.17; HRMS calcd for _{(ESI-TOF) C 29 H} 39 N 2 O [M + H] +: 431.3057; Found - 431.3054.

Synthesis of Enantiomers of Ligands L41 and L35 HCl solution (4N in dioxane, 2.6 mmol, 0.65) in a solution of tert-butanesulfinylamines L35-1c and L35-1d (320 mg, 0.65 mmol) in MeOH (5 mL) at room temperature mL) was added. The mixture was stirred for 6 hours and then the solvent was removed by reduced pressure. To the resulting foam was added CH ₂ Cl ₂ (10 mL) and Et ₃ N (263 mg, 2.6 mmol, 0.37 mL) at room temperature followed by acetic anhydride (263 mg, 2.6 mmol, 0.25 mL). After the mixture was stirred overnight (about 18 hours), it was treated with a saturated aqueous solution of Na ₂ CO ₃ . The product was extracted with dichloromethane. The combined extracts were washed with water, dried over anhydrous MgSO ₄ and concentrated in vacuo. Flash chromatography (eluent: ethyl acetate / hexane = 1/3 to 1/2) gave ligand L41 (98 mg) and the enantiomer of L35 (105 mg) as a white solid.

N-((1S, 2R) -1- (3,5-di-tert-butylphenyl) -2- (quinolin-2-yl) butyl) acetamide (L41)
^{_{[α] D 20 = -211.7 (}} c = 0.685, CHCl 3). The ¹ H and ¹³ C NMR spectral data of L41 are in agreement with the corresponding data of its enantiomer L40a. _{HRMS (ESI-TOF) C 29} H 39 N 2 Calculated ^{O [M + H] +:} 431.3057; Found: 431.3060.
Absolute stereochemistry was assigned by similarity to compound L40b.

N-((1R, 2R) -1- (3,5-di-tert-butylphenyl) -2- (quinolin-2-yl) butyl) acetamide (enantiomer of L35)
^{_{[α] D 20 = 201.6 (}} c = 0.90, CHCl 3). The ¹ H and ¹³ C NMR spectral data of the L35 enantiomers are in agreement with that of L35. _{HRMS (ESI-TOF) C 29} H 39 N 2 Calculated ^{O [M + H] +:} 431.3057; Found: 431.3060.
Absolute stereochemistry was assigned by similarity to compound L35.

N-((1S, 2S) -1- (3,5-di-tert-butylphenyl) -2- (quinolin-2-yl) propyl) acetamide (L34)
Yellow oil. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.06 (dd, J ₁ = 1.0 Hz, J ₂ = 8.4 Hz, ₁ H), 7. 91 (d, J = 8.4 Hz, 1 H), 7.74-7. 70 (m, 2 H) , 7.51-7.49 (m, 1H), 7.41 (d, J = 8.2 Hz, 1 H), 7.11 (t, J = 1.8 Hz, 1 H), 6.92 (d, J = 8.5 Hz, 1 H), 6.70 (d, J) J = 1.8 Hz, 2 H), 5.32 (dd, J ₁ = 6.1 Hz, J ₂ = 8.2 Hz, 1 H), 3.62-3.58 (m, 1 H), 2.06 (s, 3 H), 1.44 (d, J = 7.2 Hz, 3 H), 1.09 (s, 18 H); ¹³ C NMR (150 MHz, CDCl 3) δ 169.01, 163.05, 149.88, 147.19, 138.43, 136.10, 129.49, 128.84, 127.41, 126.95, 126.09, 121.70, 120.83, 120.33, 120.33 58.40, 46.41, 34.55, 31.23, 23.70, 16.63; HRMS (ESI-TOF) calcd _{C 28 H 37 N 2 O [} M + H] +: 417.2900; Found: 417.2898.
Absolute stereochemistry was assigned by similarity to compound L35.

N-((1R, 2S) -1- (3,5-di-tert-butylphenyl) -2- (quinolin-2-yl) propyl) acetamide (L34a)
Yellow oil. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.09 (dd, J ₁ = 5.8 Hz, J ₂ = 8.9 Hz, 2 H), 7. 98 (d, J = 8.4 Hz, 1 H), 7. 77-7. 72 (m, 2 H) , 7.52 (t, J = 7.3 Hz, 1 H), 7.16 (s, 1 H), 7.04 (d, J = 8.4 Hz, 1 H), 6. 92 (d, J = 1.9 Hz, 2 H), 5.33 (dd, J ₁ ¹³ C = 6.4 Hz, J ₂ = 8.8 Hz, 1 H), 3.46-3. 41 (m, 1 H), 1. 95 (s, 3 H), 1. 44 (d, J = 7.0 Hz, 3 H), 1. 15 (s, 18 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.36, 164.33, 150.36, 140.76, 136.68, 126.64, 128.39, 127.05, 126.16, 121.50, 120.86, 120.80, 58.34, 47.53, 34.67, 31.53, 19.28, HRMS _{(ESI-TOF) C 28 H} 37 N 2 calculated ^{O [M + H] +:} 417.2900; Found: 417.2908.
Absolute stereochemistry was assigned by similarity to compound L40b.

N-((1S, 2R) -1- (3,5-di-tert-butylphenyl) -2- (quinolin-2-yl) propyl) acetamide (L34b)
Yellow oil. The ¹ H and ¹³ C NMR spectral data of L34b are in agreement with the corresponding data of its enantiomer L34a. _{HRMS (ESI-TOF) C 28} H 37 N 2 Calculated ^{O [M + H] +:} 417.2900; Found: 417.2909.
Absolute stereochemistry was assigned by similarity to compound L40b.

N-((1R, 2R) -1- (3,5-di-tert-butylphenyl) -2- (quinolin-2-yl) propyl) acetamide (L34c)
Yellow oil. The ¹ H and ¹³ C NMR spectral data of L34c are in agreement with the relevant data of its enantiomer L34. _{HRMS (ESI-TOF) C 28} H 37 N 2 Calculated ^{O [M + H] +:} 417.2900; Found: 417.2908.
Absolute stereochemistry was assigned by similarity to compound L35.

N-((1S, 2S) -1- (3,5-di-tert-butylphenyl) -2- (quinolin-2-yl) pentyl) acetamide (L36)
Yellow oil. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.07-8.05 (m, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.73-7.69 (m, 2 H), 7.51-7. 48 (m, 1 H), 7.12-7.10 (m, 2H), 6.78 (d, J = 8.5 Hz, 1 H), 6.65 (d, J = 1.8 Hz, 2 H), 5. 36 (dd, J ₁ = 6.2 Hz, J ₂ = 8.1 Hz, 1 H , 3.42 (dt, J ₁ = 5.8 Hz, J ₂ = 9.6 Hz, 1 H), 2.05 (s, 3 H), 1.92-1. 79 (m, 4 H), 1. 10 (s, 18 H), 0.90 (t, J = 7.4 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 168.98, 162.10, 149.82, 147.48, 135.65, 129.35, 128.95, 127.38, 126.95, 121.55, 121.05, 120.82, 57.35, 52.55 , 32.97, 31.44, 31.24, 23.69 , 14.20; HRMS calcd for _{(ESI-TOF) C 30 H} 41 N 2 O [M + H] +: 445.3213; Found: 445.3212.
Absolute stereochemistry was assigned by similarity to compound L35.

N-((1S, 2S) -1- (3,5-di-tert-butylphenyl) -3-methyl-2- (quinolin-2-yl) butyl) acetamide (L37)
Yellow oil. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.09 (dt, J ₁ = 1.0 Hz, J ₂ = 9.0 Hz, 1 H), 7.77 (d, J = 8.5 Hz, 1 H), 7.72-7.70 (m, 2 H) , 7.51-7.49 (m, 1 H), 7.10 (t, J = 1.8 Hz, 1 H), 6. 85 (d, J = 8.1 Hz, 1 H), 6. 66 (d, J = 1.8 Hz, 2 H), 6.55 (d, J) J = 8.5 Hz, 1 H), 5.67 (dd, J ₁ = 6.0 Hz, J ₂ = 8.2 Hz, ₁ H), 3. 19 (dd, J ₁ = 6.1 Hz, J ₂ = 9.0 Hz, 1 H), 2.21-2.15 ( m, 1 H), 2.02 (s, 3 H), 1. 29 (d, J = 6.6 Hz, 3 H), 1.09 (s, 18 H), 0.88 (d, J = 6.6 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 168.74, 161.06, 149.80, 129.26, 128.93, 126.12, 126.12, 122.24, 121.58, 120.78, 60.16, 54.22, 34.54, 31.23, 27.75, 23.67, 21.73, 20.66; HRMS (ESI-TOF) calculated for _{C 30 H 41 N 2 O [} M + H] +: 445.3213; Found: 445.3218.
Absolute stereochemistry was assigned by similarity to compound L35.

N-((1R, 2S) -1- (3,5-di-tert-butylphenyl) -2-methoxy-2- (quinolin-2-yl) ethyl) acetamide (L38)
White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.09-8.07 (m, 2 H), 7.79 (dd, J ₁ = 8.1 Hz, J ₂ = 1.4 Hz, 1 H), 7.73-7.70 (m, 1 H), 7.54- 7.52 (m, 1 H), 7.34 (d, J = 8.5 Hz, 1 H), 7. 27-7. 25 (m, 1 H), 7.07 (d, J = 1.9 Hz, 2 H), 6. 90 (d, J = 9.0 Hz, 1 H) ), 5.49 (dd, J ₁ = 3.1 Hz, J ₂ = 9.1 Hz, 1 H), 4. 79 (d, J = 3.1 Hz, 1 H), 3.43 (s, 3 H), 1. 98 (s, 3 H), 1.23 (s) , 18 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 168.94, 160.00, 150.19, 147.49, 138.36, 129.58, 129.06, 127.60, 126.44, 121.46, 121.19, 118.71, 86.39, 58.04, 56.62, 34.73, 31.39. , 23.41; HRMS (ESI-TOF ) C 28 H 37 calculated _{N 2 O 2 [M + H} ] +: 433.2850; Found: 433.2847.
Absolute stereochemistry was assigned by similarity to compound L35.

N-((1S, 2S) -1- (3,5-di-tert-butylphenyl) -3-phenyl-2- (quinolin-2-yl) propyl) acetamide (L39)
White solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (d, J = 8.5 Hz, 1 H), 7.81 (d, J = 8.5 Hz, 1 H), 7.70 (t, J = 7.6 Hz, 2 H), 7.49 (t , J = 7.4 Hz, 1 H), 7.18-7.08 (m, 7 H), 6.77 (d, J = 8.5 Hz, 1 H), 6.70 (d, J = 1.8 Hz, 2 H), 5.42 (t, J = 7.3 Hz) , 1H), 3.80 (dt, J ₁ = 6.3 Hz, J ₂ = 9.4 Hz, 1 H), 3.3 ₁ (dd, J ₁ = 9.2 Hz, J ₂ = 14.2 Hz, 1 H), _3. 17 (dd, J ₁ = 5.9) Hz, J ₂ = 14.1 Hz, 1 H), 2.03 (s, 3 H), 1.00 (s, 18 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.56, 161.18, 150.15, 147.28, 139.55, 138.36, 135.73, 129.46, 128.90, 128.78, 128.33, 127.38, 126.89, 126.09, 126.96, 121.76, 121.51, 121.08, 57.61, 54.03, 36.82, 34.59, 31.22, 23.58; HRMS (ESI-TOF) C ₃₄ H ₄₁ N ₂ O calculated values [M + H] ^< +>: 493.3214; Found: 493.3215.
Absolute stereochemistry was assigned by similarity to compound L35.
General Procedure for the Synthesis of Ligands L42-L58:

Generation of Ligands from Sulfonamide L17-1 HCl (4 M in dioxane) was added dropwise to a solution of sulfinamide L17-1 in MeOH in an open flask at room temperature. When TLC indicated no starting material remained, all volatiles were removed in vacuo. A dry solvent was added to the intermediate under an atmosphere of N ₂ and a base was added to the resulting suspension to become a solution. Anhydride or acid chloride was added dropwise at room temperature. When TLC showed completion, the reaction mixture was quenched with brine and extracted three times with dichloromethane. The combined organic extracts were dried over Na ₂ SO ₄ and the solvent was removed in vacuo. The residue was purified by preparative thin layer chromatography (pTLC) on SiO ₂ using a combination of CH ₂ Cl ₂ and EtOAc as eluent.

(R) -N- (1-phenyl-2- (quinolin-2-yl) ethyl) methanesulfonamide (L42)
White solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.10 (d, J = 8.5 Hz, 1 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 8.1 Hz, 1 H), 7.73 (dd , J ₁ = 6.6 Hz, J ₂ = 8.4 Hz, 1 H), 7.54 (t, J = 7.5 Hz, 1 H), 7. 38 (d, J = 7.3 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 2 H ), 7.28 (d, J = 7.1 Hz, 1 H), 7.21 (br s, 1 H), 7.15 (d, J = 8.3 Hz, 1 H), 5.02 (dd, J ₁ = 4.3 Hz, J ₂ = 8.9 Hz, 1H), 3.41 (dd, J 1 = 4.3 Hz, J 2 = 14.4 Hz, 1H), 3.34 (dd, J 1 = 8.7 Hz, J 2 = 14.4 Hz, 1H), 2.50 (s, 3H); 13 C _{NMR (125 MHz, CDCl 3)} δ 158.24, 147.29, 141.12, 137.08, 129.99, 128.87, 128.70, 127.89, 127.57, 126.91, 126.50, 122.03, 57.73, 44.53, 41.70; HRMS (ESI-TOF) C 18 H 19 N Calculated for ₂ O ₂ S [M + H] ⁺ 327.1162, found 327.1157.

(R) -4-Methyl-N- (1-phenyl-2- (quinolin-2-yl) ethyl) benzenesulfonamide (L43)
White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.09 (d, J = 8.9 Hz, 1 H), 7.94 (d, J = 8.3 Hz, 1 H), 7.75-7.78 (m, 2 H), 7.56 (dt, J ₁ = 1.2, J ₂ = 7.8 Hz, ₁ H), 7. 36 (d, J = 8.3 Hz, 2 H), 7. 28 (dd, J ₁ = 1.3 Hz, J ₂ = 8.2 Hz, 2 H), 7.24-7. 17 (m, 4 H , 7.01 (d, J = 8.3 Hz, 1 H), 6.83 (d, J = 7.6 Hz, 2 H), 4. 66 (td, J ₁ = 3.7 Hz, J ₂ = 8.0 Hz, 1 H), 3.24-3.17 (m , 2H), 2.24 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 158.11, 147.15, 142.43, 141.24, 137.08, 136.97, 129.97, 128.34, 127.46, 127.35, 126.87, 126.81, 126.65, 126.46, 121.78, 109.95, 57.87, 44.71, 21.35; HRMS (ESI-TOF) calculated for C ₂₄ H ₂₃ N ₂ O ₂ S [M + H] ⁺ 403.1475, found 403.1484.

Methyl (R)-(1-phenyl-2- (quinolin-2-yl) ethyl) carbamate (L44)
White solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.08 (d, J = 8.5 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 7.76 (dd, J ₁ = 1.4 Hz, J ₂ = 8.2 Hz , 1H), 7.71 (ddd, J ₁ = 1.4 Hz, J ₂ = 6.8 Hz, J ₃ = 8.4 Hz, 1 H), 7.51 (ddd, J ₁ = 1.1 Hz, J ₂ = 6.8 Hz, J ₃ = 8.1 Hz , 1H), 7.23-7.27 (m, 4H), 7.21-7.17 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.58 (br s, 1H), 5.22 (br s, 1H), 3.57 (s, 3 H), 3.47 (dd, J ₁ = 5.0 Hz, J ₂ = 14.0 Hz, 1 H), 3.33 (dd, J ₁ = 7.6 Hz, J ₂ = 13.3 Hz, 1 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 158.58, 156.36, 147.58, 142.45, 129.58, 128.38, 127.52, 127.12, 126.81, 126.15, 122.05, 55.06, 51.97, 44.86, HRMS (ESI-TOF) C ₁₉ H ₁₉ Calc'd for N ₂ O ₂ [M + H] ⁺ 307.1441, found 307.1445.

Ethyl (R)-(1-phenyl-2- (quinolin-2-yl) ethyl) carbamate (L45)
White solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.08 (d, J = 8.5 Hz, 1 H), 7. 98 (d, J = 8.3 Hz, 1 H), 7. 76 (dd, J ₁ = 1.4 Hz, J ₂ = 8.1 Hz , 1H), 7.71 (ddd, J ₁ = 1.5 Hz, J ₂ = 6.9 Hz, J ₃ = 8.4 Hz, 1 H), 7. 50 (ddd, J ₁ = 1.2 Hz, J ₂ = 6.9 Hz, J ₃ = 8.1 Hz , 1H), 7.25 (d, J = 4.5 Hz, 4 H), 7.21-7.17 (m, 1 H), 7.07 (d, J = 8.4 Hz, 1 H), 6.43 (br s, 1 H), 5.24 (br s, 1H), 4.00 (q, J = 7.1 Hz, 2H), 3.47 (dd, J ₁ = 5.1 Hz, J ₂ = 14.0 Hz, 1 H), 3.34 (dd, J ₁ = 7.5 Hz, J ₂ = 14.2 Hz, 1 H), 1.15 (br s, 3 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 158.61, 155.98, 147.61, 142.26, 136.38, 129.51, 128.99, 128.36, 127.52, 127.08, 126.81, 126.11, 126.11, 122.06. 60.68, 54.92, 44.97, 29.67, 14.51; HRMS (ESI-TOF) C 20 H 21 calculated _{N 2 O 2 [M + H} ] + 321.1598, Found 321.1599.

White solid. (R)-(1-phenyl-2- (quinolin-2-yl) ethyl) isobutyl carbamate (L 46)
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.08 (d, J = 8.5 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 7.76 (dd, J ₁ = 1.3 Hz, J ₂ = 8.2 Hz , 1H), 7.71 (ddd, J ₁ = 1.4 Hz, J ₂ = 6.8 Hz, J ₃ = 8.4 Hz, 1 H), 7. 50 (ddd, J ₁ = 1.2 Hz, J ₂ = 6.9 Hz, J ₃ = 8.1, Hz, 1 H), 7.22-7. 29 (m, 4 H), 7.21-7.18 (m, 1 H), 7.09 (br s, 1 H), 6.41 (br s, 1 H), 5.23 (br s, 1 H), 3.74 (dd _{, J 1 = 6.7 Hz, J} 2 = 10.1 Hz, 2H), 3.51-3.43 (m, 1H), 3.40-3.29 (m, 1H), 1.80 (br s, 1H), 0.83 (s, 6H); 13 _{C NMR (125 MHz, CDCl 3} ) δ 158.64, 156.13, 147.60, 142.23, 136.41, 129.53, 128.95, 128.38, 127.52, 127.09, 126.82, 126.16, 126.12, 122.03, 70.88, 54.95, 45.00, 29.68, 27.91, 18.92; calculated _{HRMS (ESI-TOF) C 22} H 25 N 2 O 2 [M + H] + 349.1911, Found 349.1911.

(R)-(1-phenyl-2- (quinolin-2-yl) -ethyl) -tert-butyl carbamate (L 47)
White solid. ¹ H-NMR (600 MHz, CDCl ₃ ) δ 8.08 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 7.76 (dd, J ₁ = 1.3 Hz, J ₂ = 8.2 Hz, 1 H), 7.71 (ddd, J ₁ = 1.4 Hz, J ₂ = 6.8 Hz, J ₃ = 8.4 Hz, 1 H), 7. 50 (ddd, J ₁ = 1.2 Hz, J ₂ = 6.8 Hz, J ₃ = 8.1 Hz, 1 H), 7. 25 (d, J = 5.7 Hz, 4 H), 7. 20 (dt, J ₁ = 3.2 Hz, J ₂ = 5.6 Hz, 1 H), 7.09 (d, J = 8.4 Hz, 1 H), 6.07 ( br s, 1H), 5.21 (br s, 1H), 3.55-3.41 (m, 1H), 3.40-3.23 (m, 1H), 1.32 (s, 9H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ HRMS (ESI-TOF) C ₂₂ H ₂₅ N ₂ O ₂ 158.71, 155.21, 147.64, 142.29, 129.46, 128.36, 127.51, 127.01, 126.01, 126.17, 126.06, 122.08, 79.21, 54.55, 45.36, 28.23; Calculated value for [M + H] ⁺ 349.1911, found 349.1917.

Benzyl (R)-(1-phenyl-2- (quinolin-2-yl) ethyl) carbamate (L48)
White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.06 (d, J = 8.5 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 7.70 (t , J = 7.7 Hz, 1 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.14-7.35 (m, 10 H), 7.07 (d, J = 8.3 Hz, 1 H), 6.58 (br s, 1 H), 5.27 (d, J = 7.9 Hz , 1H), 4.93-5.07 (m, 2H), 3.48 (dd, J 1 = 4.9 Hz, J 2 = 14.2 Hz, 1H), 3.28-3.39 (m, 1H); 13 C NMR (150 MHz, CDCl ₃ ) δ 158.50, 155.72, 147.56, 142.42, 136.44, 129.98, 128.40, 128.34, 127.53, 127.15, 126.80, 126.18, 126.14, 126.14, 122.04, 66.46, 45.84; calculated _{HRMS (ESI-TOF) C 25} H 23 N 2 O 2 [M + H] + 383.1754, Found 383.1751.

(R)-(1-phenyl-2- (quinolin-2-yl) ethyl) carbamic acid (9H-fluoren-9-yl) methyl (L49)
White foam. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.11 (d, J = 8.4 Hz, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.79-7.77 (m, 2 H), 7.70 (t, J = 7.2 Hz, 1 H), 7.58 (t, J = 7.5 Hz, 1 H), 7.54-7. 45 (m, 2 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.31-7. 24 (m, 4 H), 7. 26- 7.11 (m, 2 H), 6.82 (br s, 1 H), 5.21 (br s, 1 H), 4. 29 (t, J = 9.2 Hz, 1 H), 4.22 (t, J = 8.8 Hz, 1 H), 4.17-4.09 (m, 1H), 3.56-3.44 (m, 1H), 3.41-3.26 (m, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 158.69, 155.73, 147.58, 143.94, 142.19, 141.19, 136.65, 129.69 , 128.93, 128.49, 127.62, 127.50, 127.22, 126.91, 126.24, 126.13, 125.08, 122.83, 66.59, 55.17, 47.17, 44.79; HRMS (ESI-TOF) C ₃₁ H ₃₆ N ₂ O calculated values [ M + H] ⁺ 471.2067, found 471.2073.

(R) -2,2,2-trifluoro-N- (1-phenyl-2- (quinolin-2-yl) -ethyl) acetamide (L50)
White solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 10.30 (d, J = 6.8 Hz, 1 H), 8.04 (d, J = 8.6 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 1 H), 7.78 (d , J = 8.4 Hz, 1 H, 7. 76 (t, J = 8.4 Hz, 1 H), 7.55 (ddd, J ₁ = 1.1 Hz, J ₂ = 6.8 Hz, J ₃ = 8.1 Hz, 1 H), 7.13-7.23 (m, 3 H), 7.11 (dd, J ₁ = 1.7 Hz, J ₂ = 7.8 Hz, 2 H), 7.02 (d, J = 8.3 Hz, 1 H), 5. 47 (q, J = 5.6 Hz, 1 H), 3.58 (dd, J ₁ = 4.7 Hz, J ₂ = 14.6 Hz, 1 H), 3.36 (dd, J ₁ = 5.5 Hz, J ₂ = 14.6 Hz, 1 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 158.31, _{156.45 (q, J FC = 36.6} Hz), 147.02, 139.93, 137.12, 130.14, 128.57, 128.51, 127.66, 127.49, 126.85, 126.58, 125.99, 122.49, 116.20 (d, J FC = 288.1 Hz), 53.40, 42.20; ¹⁹ F-NMR (375 MHz, CDCl ₃ ) δ -76.2; HRMS (ESI-TOF) calc'd for C ₁₉ H ₁₆ F ₃ N ₂ O [M + H] ⁺ 345.1209, found 345.1208.

(R) -2-Fluoro-N- (1-phenyl-2- (quinolin-2-yl) -ethyl) acetamide (L51)
White solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.97 (d, J = 6.5 Hz, 1 H), 8.08 (d, J = 8.5 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 7.77 (dd , J ₁ = 1.3 Hz, J ₂ = 8.2 Hz, 1 H), 7.72 (ddd, J ₁ = 1.4 Hz, J ₂ = 6.9 Hz, J ₃ = 8.3 Hz, 1 H), 7.52 (ddd, J ₁ = 1.1 Hz) _{, J 2 = 6.9 Hz, J} 3 = 8.1 Hz, 1H), 7.12-7.25 (m, 5H), 7.05 (d, J = 8.4 Hz, 1H), 5.57 (q, J = 6.5 Hz, 1H), 4.79 (d, J _FH = 47.4 Hz, 2 H), 3.55 (dd, J ₁ = 4.9 Hz, J ₂ = 14.2 Hz, 1 H), 3. 39 (dd, J ₁ = 6.5 Hz, J ₂ = 14.2 Hz, 1 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 166.97 (d, J _FC = 17.3 Hz), 158.43, 147.40, 141.16, 136.62, 129.77, 128.87, 128.41, 127.53, 127.23, 126.78, 126.21, 126.21, 122.25, 80.37 ( _{d, J FC = 186.3 Hz)} , 52.50, 43.63; 19 F NMR (375 MHz, CDCl 3) δ -225.12; HRMS (ESI-TOF) C 19 H 18 FN 2 calculated O [M ⁺ H] + 309.1398 , Found 309.1398.

(R) -N- (1-phenyl-2- (quinolin-2-yl) ethyl) propionamide (L52)
White solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.04 (dd, J ₁ = 1.1 Hz, J ₂ = 8.4 Hz, 1 H), 8.01 (d, J = 8.3 Hz, 1 H), 7.78 (dd, J ₁ = _{1.4 Hz, J 2 = 8.1 Hz} , 1H), 7.72 (ddd, J 1 = 1.9 Hz, J 2 = 6.5 Hz, J 3 = 8.4 Hz, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.52 _{(ddd, J 1 = 1.2 Hz} , J 2 = 6.9 Hz, J 3 = 8.1 Hz, 1H), 7.25-7.20 (m, 4H), 7.19-7.14 (m, 1H), 7.10 (d, J = 8.4 Hz , 1H), 5.48 (dt, J ₁ = 4.8 Hz, J ₂ = 7.4 Hz, 1 H), 3.50 (dd, J ₁ = 4.8 Hz, J ₂ = 14.0 Hz, 1 H), _3. 35 (dd, J ₁ = 7.5) _{Hz, J 2 = 14.0 Hz,} 1H), 2.25-2.20 (m, 2H), 1.11 (t, J = 7.6 Hz, 3H); 13 C NMR (125 MHz, CDCl 3): δ 172.98, 158.99, 147.40, 141.95, 136.61, 129.68, 128.63, 128.37, 127.69, 127.02, 126.21, 126.12, 122.27, 52.92, 44.28, 29.82, 9.72; HRMS (ESI-TOF) C ₂₀ H ₂₁ N ₂ O calculated value [M + H] ⁺ 305.1648, found 305.1652.

(R) -N- (1-phenyl-2- (quinolin-2-yl) ethyl) isobutyramide (L53)
White solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.05 (d, J = 8.4 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.72 ( ddd, J ₁ = 1.4 Hz, J ₂ = 7.0 Hz, J ₃ = 8.4 Hz, 1 H), 7.71 (d, J = 7.6 Hz, 1 H), 7.52 (ddd, J ₁ = 0.9 Hz, J ₂ = 7.0 Hz _{, J 3 = 8.0 Hz, 1H} ), 7.26-7.15 (m, 5H), 7.11 (d, J = 8.4 Hz, 1H), 5.46 (dt, J 1 = 4.8 Hz, J 2 = 7.6 Hz, 1H), _{3.50 (dd, J 1 = 4.8} Hz, J 2 = 14.0 Hz, 1H), 3.35 (dd, J 1 = 7.6 Hz, J 2 = 14.0 Hz, 1H), 2.42-2.36 (m, 1H), 1.12 (d , J = 6.9 Hz, 3 H), 1.06 (d, J = 6.9 Hz, 3 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 176.08, 159.06, 147.37, 142.08, 136.62, 129.70, 128.59, 128.36, 127.70, 126.97, 126.84, 126.19, 126.13, 122.30, 52.75, 44.29, 35.66, 19.47; HRMS (ESI-TOF) C 21 H 23 N 2 calculated ^{O [M + H] + 319.1805} ; Found 319.1803.

(R) -3-Methyl-N- (1-phenyl-2- (quinolin-2-yl) ethyl) butanamide (L54)
White solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.06 (d, J = 8.4 Hz, 2 H), 7.78 (d, J = 8.2 Hz, 1 H), 7.73 (t, J = 7.8 Hz, 1 H), 7.57 (d , J = 7.8 Hz, 1 H), 7.53 (t, J = 7.6 Hz, 1 H), 7.33-7.16 (m, 6 H), 5.50 (dt, J ₁ = 4.6 Hz, J ₂ = 8.2 Hz, 1 H), 3.48 (dd, J ₁ = 4.8 Hz, J ₂ = 14.0 Hz, ₁ H), 3. 36 (dd, J ₁ = 8.8 Hz, J ₂ = 14.0 Hz, 1 H), 2.05-1.90 (m, 1 H), 1.05 (d, J = 6.5 Hz, 2 H), 0.74 (d, J = 6.0 Hz, 3 H), 0.66 (d, J = 6.0 Hz, 3 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 171.87, 158.98, 147.15, 142.18 , 136.98, 129.77, 128.42, 128.19, 127.68, 126.90, 126.26, 122.02, 52.39, 53.07, 46.12, 44.43, 26.05, 22.26, 22.16; HRMS (ESI-TOF) C ₂₂ H ₂₅ N ₂ O calculated values [ M + H] ⁺ 333.1961, found 333.1966.

(R) -N- (1-phenyl-2- (quinolin-2-yl) ethyl) pivalamide (L55)
White solid. ¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.20 (d, J = 6.8 Hz, 1 H), 8.04 (d, J = 8.5 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 7.77 ( dd, J ₁ = 1.4 Hz, J ₂ = 8.2 Hz, 1 H), 7.73 (ddd, J ₁ = 1.4 Hz, J ₂ = 6.9 Hz, J ₃ = 8.4 Hz, 1 H), 7.52 (ddd, J ₁ = 1.1 _{Hz, J 2 = 6.9 Hz,} J 3 = 8.0 Hz, 1H), 7.23-7.18 (m, 2H), 7.17-7.12 (m, 3H), 7.04 (d, J = 8.3 Hz, 1H), 5.40 (dt , J ₁ = 4.6 Hz, J ₂ = 6.9 Hz, 1 H), 3.50 (dd, J ₁ = 4.6 Hz, J ₂ = 13.9 Hz, 1 H), 3.32 (dd, J ₁ = 7.1 Hz, J ₂ = 13.9 Hz , 1H), 1.19 (s, 9H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 177.74, 159.16, 147.32, 142.22, 136.60, 129.73, 128.51, 128.28, 127.70, 126.83, 126.80, 126.17, 125.96, 122.44, 52.87, 44.15, 38.69, 27.53; HRMS (ESI-TOF) calcd _{C 22 H 25 N 2 O [} M + H] + 333.1961, Found 333.1960.

(R) -N- (1-phenyl-2- (quinolin-2-yl) ethyl) benzamide (L56)
White solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.15 (d, J = 6.8 Hz, 1 H), 8. 19 (d, J = 8.4 Hz, 1 H), 8. 10 (d, J = 8.4 Hz, 1 H), 8.02 (dd , J ₁ = 1.7 Hz, J ₂ = 7.9 Hz, 2 H), 7. 87 (d, J = 8.2 Hz, 1 H), 7.84 (dd, J ₁ = 6.9 Hz, J ₂ = 8.4 Hz, 1 H), 7.62 (d , J = 7.7 Hz, 1 H), 7.58 (d, J = 7.0 Hz, 1 H), 7.54 (t, J = 7.4 Hz, 2 H), 7.33 (d, J = 7.1 Hz, 2 H), 7.30 (t, J = 7.5 Hz, 2 H), 7. 25 (t, J = 6.9 Hz, 1 H), 7. 18 (d, J = 8.4 Hz, 1 H), 5.73 (q, J = 6.4 Hz, 1 H), 3.71 (dd, J ₁ = 4.7 Hz, J ₂ = 14.0 Hz, 1 H), 3.53 (dd, J ₁ = 6.7 Hz, J ₂ = 14.1 Hz, 1 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 166.38, 159.15, 147.32, 141.85, 137.80, 134.63, 131.32, 129.86, 128.49, 128.34, 127.10, 127.00, 126.68, 126.27, 126.16, 122.57, 53.49, 43.92; HRMS (ESI-TOF) C ₂₄ H ₂₁ N ₂ O calculated value [M + H] ⁺ 353.1648, found 353.1655.

(R) -2-phenyl-N- (1-phenyl-2- (quinolin-2-yl) -ethyl) acetamide (L57)
White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.95 (d, J = 8.3 Hz, 1 H), 7.80 (dd, J ₁ = 1.1 Hz, J ₂ = 8.4 Hz, 1 H), 7.75 (dd, J ₁ = 1.5) Hz, J ₂ = 8.2 Hz, 1 H), 7. 70 (ddd, J ₁ = 1.5 Hz, J ₂ = 6.8 Hz, J ₃ = 8.4 Hz, 1 H), 7.52 (ddd, J ₁ = 1.2 Hz, J ₂ = 6.8 _{Hz, J 3 = 8.0 Hz,} 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.24-7.18 (m, 5H), 7.18-7.08 (m, 5H), 7.03 (d, J = 8.4 Hz, 1 H), 5.51 (dt, J ₁ = 4.7 Hz, J ₂ = 7.7 Hz, 1 H), 3.53 (s, 2 H), _3. 44 (dd, J ₁ = 4.8 Hz, J ₂ = 14.2 Hz, 1 H), _3. 27 ( dd, J ₁ = 7.9 Hz, J ₂ = 14.2 Hz, 1 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.28, 158.62, 147.33, 141.75, 136.47, 134.88, 129.40, 129.34, 128.96, 128.80, 128.33, 127.54, 127.09, 127.00, 126.75, 126.13, 121.97, 53.07, 44.25, 43.99; HRMS (ESI-TOF) C 25 H 23 N 2 calculated ^{O [M + H] + 367.1805} , Found 367.1803.

(R) -N- (1-phenyl-2- (quinolin-2-yl) -ethyl) cyclopropanecarboxamide (L58)
White solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.06 (d, J = 8.5 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 7.78 (dd, J ₁ = 1.4 Hz, J ₂ = 8.2 Hz , 1H), 7.73-7.69 (m, 4H), 7.52 (ddd, J 1 = 1.1 Hz, J 2 = 6.9 Hz, J 3 = 8.0 Hz, 1H), 7.25-7.20 (m, 4H), 7.18-7.15 (m, 1 H), 7.10 (d, J = 8.4 Hz, 1 H), 5. 49 (dt, J ₁ = 5.0 Hz, J ₂ = 7.3 Hz, 1 H), 3.50 (dd, J ₁ = 5.0 Hz, J ₂ = 14.0 Hz, ₁ H), 3. 37 (dd, J ₁ = 7.4 Hz, J ₂ = 14.0 Hz, 1 H), 1.45-1. 39 (m, 1 H), 0.90-0.79 (m, 2 H), 0.70-0. 61 (m, 2 H) ¹³ C NMR (125 MHz, CDCl ₃ ) δ 172.79, 159.01, 147.45, 141.98, 126.60, 128.36, 127.67, 127.00, 126.85, 126.26, 126.15, 122.28, 53.23, 44.36, 14.89, 7.03, 6.98 ; HRMS (ESI-TOF) C 21 H 21 N 2 calculated ^{O [M + H] + 317.1648} ; Found 317.1649.
Synthesis of L59 ligand

Synthesis of L59-2
n-Butyllithium (1.50 mL, 1.6 M solution in hexane, 2.40 mmol) was added to quinaldine (0.35 mL, 2.59 mmol) in 20 mL of THF. After 90 minutes, a solution of L59-1 (679 mg, 2.00 mmol) in THF (2.0 mL) was added at -78 ° C., leading the solution along the inside wall of the flask. After 90 minutes, the dry ice was removed and the solution was allowed to return to room temperature for 5 hours. Aqueous work-up gave 1.179 g of crude product (dr ̃1: 10), subjected to preparative TLC (EtOAC / CH ₂ Cl ₂ = 1/8, developed 3 ×) TBS protected sulfonamide (723 mg, 1.50 mmol, 75%). In an open flask, tetrabutylammonium fluoride (TBAF) (0.72 mL, 1 M in THF, 0.72 mmol) was added dropwise to a solution of TBS protected sulfonamide (172 mg, 0.36 mmol) in THF (5 mL). After 45 minutes, the reaction mixture was diluted with CH ₂ Cl ₂ (25 mL) and brine (50 mL). After phase separation, the aqueous phase was extracted with CH ₂ Cl ₂ (3 × 5 mL). The combined organic extracts are dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product obtained is subjected to preparative TLC (EtOAc / CH ₂ Cl ₂ = 1/1) L59-2 (122 mg, 93) %) Got. ¹ H NMR (500 MHz, CDCl ₃ ) δ 10.11 (br s, 1 H), 8. 10 (d, J = 8.5 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 7. 76 (dd, J ₁ = _{1.4 Hz, J 2 = 8.2 Hz} , 1H), 7.71 (ddd, J 1 = 1.5 Hz, J 2 = 6.9 Hz, J 3 = 8.4 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1 H), 7.08 (dd, J ₁ = 1.6 Hz, J ₂ = 7.5 Hz, 1 H), 6. 84 (dt, J ₁ = 1.6 Hz, J ₂ = 7.6 Hz, 1 H), 6.67 _{(dt, J 1 = 1.1 Hz} , J 2 = 7.4 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 5.20 (d, J = 7.9 Hz, 1H), 5.07 (q, J = 7.6 Hz , 1H), 3.77 (dd, J 1 = 8.0 Hz, J 2 = 14.5 Hz, 1H), 3.46 (dd, J 1 = 6.8 Hz, J 2 = 14.5 Hz, 1H), 1.07 (s, 9H); 13 _{C NMR (125 MHz, CDCl 3} ) δ 159.38, 154.97, 147.29, 136.32, 129.65, 128.90, 128.31, 127.89, 127.58, 127.52, 126.80, 126.05, 122.40, 119.32, 116.98, 59.46, 56.16, 45.09, 22.51.

Synthesis of L59
L59-2 (119 mg, 0.32 mmol) in MeOH (10 mL) was stirred with HCl (0.50 mL, 4 M solution in dioxane, 2 mmol) for 30 minutes. The intermediate is dissolved in CH ₂ Cl ₂ (5.0 mL) and pyridine (0.52 mL) under N ₂ atmosphere and stirred with a solution of triphosgene (126 mg, 0.43 mmol) in CH ₂ Cl ₂ (1.0 mL) for 4 hours, At this point the reaction mixture began to turn brown. After aqueous workup with CuSO ₄ saturated aqueous solution, the residue was subjected to preparative TLC (EtOAc / CH ₂ Cl ₂ = 1/1) to give L59 as a yellow foam (22 mg, 23%).

(R) -4- (quinolin-2-ylmethyl) -3,4-dihydro-2H-benzo [e] [1,3] oxazin-2-one (L59)
¹ H NMR (600 MHz, CDCl ₃ ) δ 8.11 (d, J = 8.4 Hz, 1 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.81 (dd, J ₁ = 1.4 Hz, J ₂ = 8.2 Hz , 1H), 7.74 (ddd, J ₁ = 1.5 Hz, J ₂ = 6.9 Hz, J ₃ = 8.4 Hz, 1 H), 7.55 (dt, J ₁ = 1.2 Hz, J ₂ = 6.8 Hz, J ₃ = 7.4 Hz , 1H), 7.31 (dt, J ₁ = 1.7 Hz, J ₂ = 7.8 Hz, 1 H), 7.21 (d, J = 8.3 Hz, 2 H), 7. 16 (dt, J ₁ = 1.2 Hz, J ₂ = 7.4 Hz , 1H), 7.08 (dd, J ₁ = 1.1 Hz, J ₂ = 8.2 Hz, 1 H), 7.04 (br s, 1 H), 5.41 (dt, J ₁ = 2.7 Hz, J ₂ = 10.4 Hz), 3.49 ( dd, J ₁ = 3.2 Hz, J ₂ = 16.4 Hz, 1 H), 3.41 (dd, J ₁ = 10.2 Hz, J ₂ = 16.4 Hz, 1 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 157.52, 150.29 , 149.66, 147.45, 136.88, 129.90, 129.92, 126.90, 126.01, 126.51, 125.91, 124.82, 120.55, 116.83, 51.64, 46.30; HRMS (ES-TOF) C ₁₈ H ₁₄ N ₂ O ₂ calculated values [M + H] ^< +> 291.1128, found 291.1121.

Synthesis of racemic ligand L 60 [Qian, et al., J. Am. Chem. Soc. 132, 3650-3651 (2010); and Hesp, et al., Org. Lett. 14, 2304-2307 (2012) ]

Pd (OAc) ₂ (2.8 mg, 0.13 mmol), 1, 10-phenanthroline (1, 10-phen; 3.4 mg, 0.19 mmol) and dry CH ₂ Cl ₂ (1.0 mL) under N ₂ atmosphere, stir bar bar Was added to a screw cap vial containing and the mixture continued to stir at 40.degree. C. for 0.5 h. After evaporation of CH ₂ Cl ₂ , quinaldine (0.10 mL, 0.74 mmol), L60-1 (95 mg, 0.3 mmol), and dry THF (1.5 mL) were added to the vial. The mixture was kept stirring at 120 ° C. for 26 hours. The solvent was evaporated under reduced pressure and the residue was purified by pTLC (EtOAc / CH ₂ Cl ₂ = 1/50) to give L60-2 (91 mg, 71%). ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.07 (d, J = 8.3 Hz, 2 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.93 (dd, J ₁ = 1.1 Hz, J ₂ = 8.4 Hz , 1H), 7.78 (dd, J ₁ = 1.4 Hz, J ₂ = 8.0 Hz, 1 H), 7. 70 (d, J = 7.4 Hz, 1 H), 7. 68 (ddd, J ₁ = 1.5 Hz, J ₂ = 6.9 Hz , J ₃ = 8.4 Hz, 1 H, 7.52 (ddd, J ₁ = 1.2 Hz, J ₂ = 6.9 Hz, J ₃ = 8.1 Hz, 1 H), 7. 38 (dt, J ₁ = 1.4 Hz, J ₂ = 7.5 Hz , 1H), 7.35 (dt, J ₁ = 1.1 Hz, J ₂ = 7.4 Hz, 1 H), 7. 28 (dd, J ₁ = 3.0 Hz, J ₂ = 8.3 Hz, 3 H), 6.99 (dd, J ₁ = 1.0) Hz, J ₂ = 7.6 Hz, 1 H), 6.03 (dd, J ₁ = 3.4 Hz, J ₂ = 8.8 Hz, 1 H), 4.31 (dd, J ₁ = 3.4 Hz, J ₂ = 14.6 Hz, 1 H), 3.44 (dd, J ₁ = 8.8 Hz, J ₂ = 14.5 Hz, 1 H), 2.38 (s, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 166.67, 156.75, 147.62, 145.90, 144.97, 136.32, 135.95, 133.57, 129.51, 129.49, 129.26, 128.70, 128.33, 127.51, 126.86, 126.27, 124.66, 123.70, 122.09, 61.39, 43.06, 21.61.

Under a N ₂ atmosphere, finely chopped sodium metal (26.7 mg, 1.16 mmol) and naphthalene (170 mg, 1.33 mmol) were suspended in freshly distilled DME (2.0 mL) and stirred for 2 hours at room temperature . 1.00 mL of this dark green solution was added dropwise to a solution of L60-2 (71 mg, 0.17 mmol) in DME (1.0 mL) over 15 minutes at −78 ° C. under N ₂ atmosphere. After addition, the reaction mixture solidified after a deep green color persisted for 3 minutes. The surface of the green solid was covered with MeOH (1.0 mL) by dropwise addition and allowed to warm slowly to room temperature. The resulting orange solution was diluted with EtOAc (20 mL) and brine (80 mL). After phase separation, the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic extracts were dried over MgSO ₄ and concentrated in vacuo. The residue was subjected to preparative _{TLC (EtOAc / CH 2 Cl 2} = 1/3) to give the L60 as a yellow foam (15mg, 33%). In addition, 14 mg (8%) of starting material L60-2 was recovered.

3- (quinolin-2-ylmethyl) isoindolin-1-one (L60)
¹ H NMR (600 MHz, CDCl ₃ ) δ 8.12 (dd, J ₁ = 0.8 Hz, J ₂ = 8.4 Hz, 1 H), 8.08 (dd, J ₁ = 1.0 Hz, J ₂ = 8.4 Hz, 1 H), 7. 90 (dt, J ₁ = 1.0 Hz, J ₂ = 7.5 Hz, 1 H), 7.82 (dd, J ₁ = 1.4 Hz, J ₂ = 8.1 Hz, ₁ H), 7. 75 (ddd, J ₁ = 1.4 Hz, J ₂ = _{6.9 Hz, J 3 = 8.4 Hz} , 1H), 7.60 (dt, J 1 = 1.2 Hz, J 2 = 7.5 Hz, 1H), 7.55 (ddd, J 1 = 1.2 Hz, J 2 = 6.8 Hz, J 3 = 8.1 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 1 H), 7. 49 (dd, J ₁ = 0.9 Hz, J ₂ = 7.5 Hz, 1 H), 7. 45 (br s, 1 H), 7. 28 (d, J = 8.4 Hz, 1 H), 5. 30 (dd, J ₁ = 3.4 Hz, J ₂ = 10.6 Hz, 1 H), _3. 68 (dd, J ₁ = 3.4 Hz, J ₂ = 15.8 Hz, 1 H), 3.09 (dd, J ₁ = 10.6 Hz, J ₂ = 15.8 Hz, 1 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.90, 158.35, 147.75, 147.18, 136.68, 132.29, 131.75, 129.01, 128.34, 127.60, 126.93, 126.40 , 124.01, 122.38, 121.65, 55.52, 43.03.
Synthesis of pyridine and imazoline (imazoline) ligands with two chiral centers

Preparation of mono N-protected aminomethyl oxazoline ligand

General procedure for the preparation of oxazoline ligands [Lee et al., Org. Lett. 2005, 7: 1837-1839]:
Synthesis of Fmoc protected oxazolines
To a solution of N-Fmoc protected amino acid in DCM (200mL) (10.0mmol), amino alcohol _{(10.0mmol), PPh 3 (30.0mmol} ) and N, N- diisopropylethylamine (DIPEA) (30.0mmol) at 0 ℃ Added. CCl ₄ (50.0 mmol) was added dropwise by syringe pump over 3 hours. The ice bath was removed after the addition and the reaction mixture was stirred at room temperature for 24 hours. The solvent was then removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired oxazoline.
Deprotection of Fmoc protected oxazoline
To a solution of N-Fmoc protected oxazoline (6.0 mmol) in MeOH (30 mL), piperidine was added dropwise at 0 ° C. The ice bath was removed after addition and the reaction was stirred at room temperature. The reaction progress was monitored by TLC. After completion, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain the desired amine.

Description of Protection of the Amine-Acetyl Group Triethylamine (4.5 mmol) was added to a solution of the amine (3.0 mmol) in dry DCM (20 mL). Acetic anhydride (4.5 mmol) was added slowly at 0 ° C. in 10 minutes. The ice bath was removed after addition and the reaction was stirred at room temperature. The reaction progress was monitored by TLC. After completion, the reaction was quenched at 0 ° C. with saturated NaHCO ₃ (aq). The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over anhydrous NaSO _4, filtered and concentrated in vacuo. The crude reaction mixture was purified by silica gel column chromatography to obtain the desired oxazoline ligand.
Note: If racemic amino alcohol is used for ligand synthesis, two diastereomers can be separated by silica gel column chromatography in the final step.
Complete characterization of the ligand

N-((1S, 2S) -1- (4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide (L63)
L63 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 6.29 (br, 1 H, NH), 4. 66 (dd, J = 9.0, 4.8 Hz, 1 H), 4.35-4.27 (m, 2 H), 3.84 (t, J = 9.6 Hz, 2 H), 2.16-2.11 (m, 1 H), 2.03 (s, 3 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.92 (d, J = 7.2 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 169.75, 167.70, 68.02, 53.75, 52.31, 31.35, 23.24, 18.72, 17.70;
HRMS (ESI-TOF): m / z C 9 H 17 N 2 O 2 + Calculated [M ⁺ H] + 185.1285, Found 185.1288.

(S) -N-((4-benzyl-4,5-dihydrooxazol-2-yl) methyl) acetamide (L64)
L64 was prepared according to the general procedure and purified by silica gel column chromatography to give a pale yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.32-7.29 (m, 2 H), 7.25-7.22 (m, 1 H), 7.20-7.19 (m, 2 H), 6.24 (br, 1 H, NH), 4.43- 4.37 (m, 1H), 4.27 (t, J = 9.0 Hz, 1H), 4.06-4.02 (m, 3H), 3.08 (dd, J = 13.8, 5.4 Hz, 1H), 2.67 (dd, J = 13.8, 8.4 Hz, 1 H), 2.04 (s, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 169.97, 164.62, 137.48, 129.13, 128.57, 126.65, 72.59, 66.88, 41.55, 37.03, 22.98;
HRMS (ESI-TOF): m / z C 13 H 17 N 2 O 2 + Calculated [M ⁺ H] + 233.1285, Found 233.1285.

N-((1S, 2S) -1-((S) -4-benzyl-4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide (L62)
L62 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, acetone-d ⁶ ): δ 7.30-7.25 (m, 4 H), 7.21-7.18 (m, 1 H), 7.12 (br, 1 H, NH), 4.58 (dd, J = 9.6, 7.8) Hz, 1H), 4.38-4.33 (m, 1H), 4.23 (t, J = 8.4 Hz, 1 H), 3. 98 (dd, J = 7.8, 7.2 Hz, 1 H), 2. 91 (dd, J = 13.8, 6.0 Hz) , 1H), 2.70 (dd, J = 13.8, 7.2 Hz, 1H), 1.94 (s, 3H), 1.79-1.75 (m, 1H), 1.52-1.46 (m, 1H), 1.21-1.15 (m, 1H) ), 0.89-0.87 (m, 6H);
¹³ C NMR (150 MHz, acetone-d ⁶ ): 169.53, 166.81, 139.33, 130.30, 129.09, 127.05, 72.43, 67.52, 42.30, 38.74, 25.80, 22.85, 15.80, 11.78;
HRMS (ESI-TOF): m / z C 17 H 25 N 2 O 2 + Calculated [M ⁺ H] + 289.1911, Found 289.1906.

N-((S) -1-((S) -4-benzyl-4,5-dihydrooxazol-2-yl) -2-methylpropyl) benzamide (L65)
L65 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.85-7.83 (m, 2H), 7.53 (tt, J = 7.2, 1.8 Hz, 1 H), 7.48-7.45 (m, 2H), 7.27-7.25 (m, 2) 2H), 7.21 (tt, J = 7.2, 1.8 Hz, 1H), 7.18-7.16 (m, 2H), 6.83 (br, 1H, NH), 4.81 (dd, J = 8.4, 4.8 Hz, 1H), 4.42 -4.37 (m, 1H), 4.27 (t, J = 8.4 Hz, 1 H), 4.07 (dd, J = 8.4, 7.2 Hz, 1 H), 3.01 (dd, J = 13.8, 6.0 Hz, 1 H), 2.68 ( dd, J = 13.8, 7.8 Hz, 1 H), 2.26-2.20 (m, 1 H), 1.00 (d, J = 7.2 Hz, 3 H), 0.98 (d, J = 6.6 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 166.99, 166.93, 137.38, 131.58, 129.28, 128.47, 128.59, 126.56, 126.45, 66.82, 52.83, 41.76, 31.79, 18.82, 17.90;
HRMS (ESI-TOF): m / z C 21 H 25 N 2 O 2 + Calculated [M ⁺ H] + 337.1911, Found 337.1911.

((S) -1-((S) -4-Benzyl-4,5-dihydrooxazol-2-yl) -2-methylpropyl) carbamic acid tert-butyl (L66)
L66 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.30-7.28 (m, 2 H), 7.23-7.18 (m, 3 H), 5.08 (br, 1 H, NH), 4.40-4.35 (m, 1 H), 4.26 (m, 1 H) dd, J = 9.0, 4.8 Hz, 1 H), 4.20-4.17 (m, 1 H), 4.02 (t, J = 8.4 Hz, 1 H), 3.07 (dd, J = 13.8, 5.4 Hz, 1 H), 2.65 (dd , J = 13.8, 8.4 Hz, 1 H), 2.09-2.03 (m, 1 H), 1.46 (s, 9 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.89 (d, J = 6.6 Hz, 3 H) ;
¹³ C NMR (150 MHz, CDCl ₃ ): 167.11, 155.61, 137.67, 129.24, 128.49, 126.52, 79.51, 72.04, 66.94, 53.96, 41.63, 31.45, 28.32, 18.86, 17.54;
HRMS (ESI-TOF): m / z C 19 H 29 N 2 O 3 + Calculated [M ⁺ H] + 333.2173, Found 333.2175.

N-((1S, 2S) -1-((S) -4-benzyl-4,5-dihydrooxazol-2-yl) -2-methylbutyl) methanesulfonamide (L67)
L67 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.32-7.30 (m, 2 H), 7.25-7.23 (m, 1 H), 7.20-7.19 (m, 2 H), 4.99 (br, 1 H, NH), 4.45 4.40 (m, 1H), 4.30 (dt, J = 8.4, 1.2 Hz, 1 H), 4.08 (dd, J = 8.4, 7.2 Hz, 1 H), 4.01 (dd, J = 9.6, 5.4 Hz, 1 H), 3.04 (dd, J = 13.8, 6.0 Hz, 1H), 2.91 (s, 3H), 2.69 (dd, J = 13.8, 8.4 Hz, 1H), 1.87-1.81 (m, 1H), 1.50-1.44 (m, 1H) ), 1.19-1.12 (m, 1 H), 0.98 (d, J = 7.2 Hz, 3 H), 0.91 (t, J = 7.8 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 166.52, 137.36, 129.17, 128.63, 126.73, 72.78, 66.90, 56.28, 41.57, 40.96, 38.32, 24.34, 15.44, 11.46;
HRMS (ESI-TOF): m / z C 16 H 25 FN 2 O 3 S + Calculated [M ⁺ H] + 325.1580, Found 325.1580.

N-((1S, 2S) -1-((S) -4-benzyl-4,5-dihydrooxazol-2-yl) -2-methylbutyl) -4-methylbenzenesulfonamide (L68)
L68 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.77-7.75 (m, 2H), 7.29-7.27 (m, 4H), 7.23-7.21 (m, 1H), 7.07-7.06 (m, 2H), 5.17 (m, 2H) br, 1H, NH), 4.08-4.03 (m, 1H), 3.93-3.88 (m, 2H), 3.72 (dd, J = 8.4, 7.2 Hz, 1 H), 2.73 (dd, J = 13.8, 6.0 Hz, 1H), 2.41 (s, 3H), 2.09 (dd, J = 13.8, 8.4 Hz, 1H), 1.77-1.70 (m, 1H), 1.51-1.45 (m, 1H), 1.20-1.13 (m, 1H) , 0.92 (d, J = 6.6 Hz, 3 H), 0.88 (t, J = 7.8 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 165.57, 143.30, 137.61, 137.31, 129.46, 128.60, 127.60, 126.61, 72.67, 66.84, 55.92, 41.37, 38.71, 24.56, 21.51, 15.24, 11.30;
HRMS (ESI-TOF): m / z C 22 H 29 N 2 O 3 S + Calculated [M ⁺ H] + 401.1893, Found 401.1895.

N-((1S, 2S) -1-((S) -4- (2,6-difluorobenzyl) -4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide (L69)
L69 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.21-7.17 (m, 1 H), 6.89-6.85 (m, 2 H), 6.12 (br, 1 H, NH), 4.63 (dd, J = 8.4, 5.4 Hz, 1H), 4.41-4.36 (m, 1H), 4.25 (t, J = 9.0 Hz, 1H), 4.11 (dd, J = 9.0, 6.0 Hz, 1H), 2.98 (dd, J = 13.8, 6.0 Hz, 1H ), 2.83 (dd, J = 13.8, 7.2 Hz, 1 H), 2.03 (s, 3 H), 1.86-1.81 (m, 1 H), 1.51-1. 44 (m, 1 H), 1.18- 1. 10 (m, 1 H), 0.91 (t, J = 7.8 Hz, 3 H), 0.88 (d, J = 6.6 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 169.48, 167.24, 161.68 (dd, J = 245.0, 8.7 Hz), 128.37 (t, J = 8.7 Hz), 113.55 (t, J = 19.8 Hz), 111.19 (d , J = 21.9 Hz), 72.36, 65.23, 51.73, 38.21, 28.43, 25.14, 23.28, 15.04, 11.66;
¹⁹ F NMR (376 MHz, CDCl ₃ ): δ -114.36 (s, 2F);
HRMS (ESI-TOF): m / z C 17 H 23 F 2 N 2 O 2 + Calculated [M ⁺ H] + 325.1722, Found 325.1729.

N-((1S, 2S) -1-((S) -4-([1,1'-biphenyl] -4-ylmethyl) -4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide (L70)
L70 was prepared according to the general procedure and purified by silica gel column chromatography to give a pale yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.58 (d, J = 9.0 Hz, 2 H), 7.53 (d, J = 8.4 Hz, 2 H), 7.43 (t, J = 7.8 Hz, 2 H), 7.34 ( t, J = 7.2 Hz, 1 H), 7. 26 (d, J = 8.4 Hz, 2 H), 6. 13 (br, 1 H, NH), 4. 68 (dd, J = 8.4, 5.4 Hz, 1 H), 4.43-4. 38 (m , 1H), 4.25 (t, J = 8.4 Hz, 1 H), 4.07 (dd, J = 9.0, 6.6 Hz, 1 H), 3.08 (dd, J = 13.8, 6.0 Hz, 1 H), 2.71 (dd, J = 13.8, 7.2 Hz, 1 H), 2.04 (s, 3 H), 1. 88-1. 84 (m, 1 H), 1.52-1. 45 (m, 1 H), 1. 19-1.12 (m, 1 H), 0.93-0.90 (m, 6 H) ;
¹³ C NMR (150 MHz, CDCl ₃ ): 169.51, 166.90, 140.78, 136.51, 129.62, 128.75, 127.19, 126.98, 72.30, 66.83, 51.78, 41.38, 38.09, 25.09, 23.34, 15.18, 11.68;
HRMS (ESI-TOF): m / z C 23 H 29 N 2 O 2 + Calculated [M ⁺ H] + 365.2224, Found 365.2225.

N-((1S, 2S) -1-((S) -4-((4-fluoro- [1,1'-biphenyl] -3-yl) methyl) -4,5-dihydrooxazol-2-yl ) -2-Methylbutyl) -acetamide (L71)
L71 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.52 (d, J = 8.4 Hz, 2 H), 7.44-7. 39 (m, 4 H), 7.34 (t, J = 7.2 Hz, 1 H), 7. 10 (t, J = 9.0 Hz, 1 H), 6.12 (br, 1 H, NH), 4. 65 (dd, J = 8.4, 4.8 Hz, 1 H), 4.44-4. 41 (m, 1 H), 4.28 (t, J = 9.0 Hz, 1 H) , 4.10 (dd, J = 9.0, 6.6 Hz, 1 H), 3.03 (dd, J = 13.8, 6.0 Hz, 1 H), 2. 84 (dd, J = 13.8, 7.2 Hz, 1 H), 1.93 (s, 3 H), 1.86-1.80 (m, 1H), 1.50-1.43 (m, 1H), 1.17-1.10 (m, 1H), 0.90 (t, J = 7.2 Hz, 3H), 0.88 (d, J = 7.2 Hz, 3H) ;
¹³ C NMR (150 MHz, CDCl ₃ ): 169.48, 167.15, 160.84 (d, J = 242.9 Hz), 140.09, 137.34, 130.56 (d, J = 4.4 Hz), 128.81, 127.30, 127.11 (d, J = 8.9) Hz), 126.95, 124.79 (d, J = 17.6 Hz), 115.70 (d, J = 24.0 Hz), 72.39, 65.65, 51.75, 38.12, 35.16, 25.12, 23.12, 15.09, 11.66;
¹⁹ F NMR (376 MHz, CDCl ₃ ): δ -120.61 (s, 1 F);
HRMS (ESI-TOF): m / z C 23 H 28 FN 2 O 2 + Calculated [M ⁺ H] + 383.2129, Found 383.2130.

N-((1S, 2S) -2-Methyl-1-((S) -4- (2,4,6-triisopropyl-benzyl) -4,5-dihydrooxazol-2-yl) butyl) acetamide ( L72)
L72 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 6.99 (s, 2 H), 6.21 (br, 1 H, NH), 4.74 (dd, J = 8.4, 4.2 Hz, 1 H), 4.28 (t, J = 8.4 Hz , 1H), 4.25-4.20 (m, 1H), 4.04 (dd, J = 8.4, 6.6 Hz, 1H), 3.22-3.15 (m, 2H), 2.98 (dd, J = 14.4, 7.8 Hz, 1H), 2.88-2.84 (m, 1H), 2.79 (dd, J = 14.4, 6.6 Hz, 1H), 2.01 (s, 3H), 1.91-1.86 (m, 1H), 1.50-1.44 (m, 1H), 1.25- 1.22 (m, 18 H), 1.18-1.12 (m, 1 H), 0.92 (t, J = 7.2 Hz, 3 H), 0.89 (d, J = 6.6 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 169.34, 166.49, 147.05, 128.79, 121.18, 72.42, 67.37, 51.87, 38.39, 34.08, 32.98, 29.42, 25.11, 24.48, 24.22, 23.98, 23.39, 15.09, 11.79 ;
HRMS (ESI-TOF): m / z C 26 H 43 N 2 O 2 + Calculated [M ⁺ H] + 415.3319, Found 415.3319.

N-((1S, 2S) -1-((S) -4-((4,4 ′ ′-Difluoro- [1,1 ′: 3 ′, 1 ′ ′-terphenyl] -2′-yl)) Methyl) -4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide (L73)
L73 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.34-7.30 (m, 5 H), 7.20 (d, J = 7.2 Hz, 2 H), 7.13-7.10 (m, 4 H), 5. 90 (br, 1 H, NH) , 4.51 (dd, J = 8.4, 4.8 Hz, 1 H), 3. 76 (t, J = 9.0 Hz, 1 H), 3. 70-3. 65 (m, 1 H), 3. 44 (t, J = 7.8 Hz, 1 H), 3.02 (3.0 dd, J = 14.4, 7.2 Hz, 1 H), 2. 78 (dd, J = 14.4, 7.2 Hz, 1 H), 1. 96 (s, 3 H), 1.71-1.63 (m, 1 H), 1.31-1.25 (m, 1 H) , 1.03-0.96 (m, 1 H), 0.82 (t, J = 7.2 Hz, 3 H), 0.71 (d, J = 7.2 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 169.18, 165.76, 162.01 (d, J = 245.0 Hz), 142.31, 137.95 (d, J = 4.4 Hz), 133.27, 130.94 (d, J = 6.6 Hz), 130.13 , 126.30, 115.32 (d, J = 19.7 Hz), 72.09, 65.20, 51.64, 38.12, 35.48, 24.90, 23.27, 14.96, 11.57;
¹⁹ F NMR (376 MHz, CDCl ₃ ): δ -115.42 (s, 2F);
HRMS (ESI-TOF): m / z C 29 H 31 F 2 N 2 O 2 + Calculated [M ⁺ H] + 477.2348, Found 477.2345.

N-((1S, 2S) -1-((S) -4-benzyl-4-methyl-4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide (L74)
L74 was prepared using the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.28-7.22 (m, 3 H), 7.15 (d, J = 7.8 Hz, 2 H), 6.11 (br, 1 H, NH), 4.53 (dd, J = 8.4, 4.8 Hz, 1 H), 4.20 (d, J = 8.4 Hz, 1 H), 3.82 (d, J = 8.4 Hz, 1 H), 2. 85 (d, J = 13.2 Hz, 1 H), 2. 78 (d, J = 13.8 Hz , 1H), 2.05 (s, 3H), 1.84-1.79 (m, 1H), 1.47-1.41 (m, 1H), 1.32 (s, 3H), 1.16-1.08 (m, 1H), 0.90 (t, J = 7.8 Hz, 3 H), 0.87 (d, J = 6.6 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 169.35, 165.37, 136.40, 128.08, 126.66, 76.84, 70.29, 51.49, 46.66, 38.16, 27.19, 25.08, 23.33, 15.02, 11.70;
HRMS (ESI-TOF): m / z C 18 H 27 N 2 O 2 + Calculated [M ⁺ H] + 303.2067, Found 303.2068.

N-((1S, 2S) -1-((S) -4- (tert-butyl) -4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide (L75)
L75 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 6.14 (br, 1H, NH), 4.67-4.64 (m, 1H), 4.22-4.18 (m, 1H), 4.13-4.09 (m, 1H), 3.85- 3.82 (m, 1 H), 4.01 (t, J = 7.8 Hz, 1 H), 3.92-3.88 (m, 1 H), 2.03 (s, 3 H), 1. 88-1.84 (m, 1 H), 1.54-1. 47 (m, 1 H) 1 H), 1.20-1. 13 (m, 1 H), 0.94-0.90 (m, 6 H), 0.87 (s, 9 H);
¹³ C NMR (150 MHz, CDCl ₃ ): δ 169.47, 166.06, 75.18, 69.07, 51.87, 38.13, 33.58, 25.74, 25.15, 23.30, 15.16, 11.68;
HRMS (ESI-TOF): m / z C 14 H 27 N 2 O 2 + Calculated [M ⁺ H] + 255.2067, Found 255.2068.

N-((1S, 2S) -1- (4,4-dibenzyl-4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide (L76)
L76 was prepared according to the general procedure and purified by silica gel column chromatography to give a pale yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.28-7.15 (m, 10H), 5.86 (br, 1H, NH), 4.38 (dd, J = 9.0, 5.4 Hz, 1H), 4.10-4.04 (m, 10) 2H), 3.10 (d, J = 13.8 Hz, 1H), 3.03 (d, J = 13.8 Hz, 1H), 2.83 (dd, J = 13.2, 10.8 Hz, 2H), 2.01 (s, 3H), 1.59- 1.54 (m, 1 H), 1.20-1. 15 (m, 1 H), 0.94-0.86 (m, 1 H), 0.76 (t, J = 7.8 Hz, 3 H), 0.60 (d, J = 6.6 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 169.10, 165.84, 136.51, 136.39, 130.92, 130.70, 128.09, 128.05, 126.52, 126.56, 73.66, 72.67, 51.55, 46.51, 38.03, 24.79, 23.30, 11.43, 11.41 ;
HRMS (ESI-TOF): m / z C 24 H 31 N 2 O 2 + Calculated [M ⁺ H] + 379.2380, Found 379.2383.

N-((1S, 2S) -1-((4S, 5S) -4,5-diphenyl-4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide (L77)
L77 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.42-7.26 (m, 8 H), 7.20 (d, J = 7.8 Hz, 2 H), 6.26 (br, 1 H, NH), 5. 29 (d, J = 8.4 Hz , 1H), 5.04 (d, J = 8.4 Hz, 1 H), 4.94 (dd, J = 8.4, 4.2 Hz, 1 H), 2.06-1.99 (m, 1 H), 2.03 (s, 3 H), 1.67-1.62 ( m, 1 H), 1.30-1. 22 (m, 1 H), 1.05 (d, J = 6.6 Hz, 3 H), 0.99 (t, J = 7.2 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 169.79, 167.08, 141.20, 139.66, 128.89, 128.60, 127.92, 126.68, 125.79, 89.92, 77.93, 52.00, 38.16, 24.99, 23.31, 15.54, 11.76;
HRMS (ESI-TOF): m / z C 22 H 27 N 2 O 2 + Calculated [M ⁺ H] + 351.2067, Found 351.2067.

N-((1S, 2S) -1-((S) -4-benzhydryl-4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide (L78)
L78 was prepared according to the general procedure and purified by silica gel column chromatography to give a pale yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.31-7.18 (m, ¹⁰ H), 6.02 (br, 1 H, NH), 4. 90-4.86 (m, 1 H), 4.56 (dd, J = 9.0, 4.8 Hz, 1H), 4.31 (t, J = 9.0 Hz, 1H), 4.02 (dd, J = 9.0, 7.2 Hz, 1H), 3.92 (d, J = 9.0 Hz, 1H), 2.10-2.04 (m, 1H), 1.99 (s, 3 H), 1.67-1. 57 (m, 2 H), 0.91 (t, J = 7.2 Hz, 3 H), 0.87 (d, J = 7.2 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 169.77, 167.19, 142.05, 141.57, 128.63, 128.50, 128.30, 126.64, 126.56, 71.98, 69.23, 56.95, 52.45, 31.41, 23.28, 18.82, 17.83;
HRMS (ESI-TOF): m / z C 23 H 29 N 2 O 2 + Calculated [M ⁺ H] + 365.2224, Found 365.2224.

N-((1S, 2S) -1-((S) -4-((benzyloxy) methyl) -4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide (L79)
L79 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.36-7.27 (m, 5 H), 6.17 (br, 1 H, NH), 4.68 (dd, J = 9.0, 5.4 Hz, 1 H), 4.56-4.52 (m, 5 2H), 4.33-4.29 (m, 2H), 4.18 (t, J = 6.0 Hz, 1 H), 3.61 (dd, J = 9.6, 4.8 Hz, 1 H), 3.39 (dd, J = 9.6, 6.6 Hz, 1 H) ), 2.00 (s, 3 H), 1. 87-1.81 (m, 1 H), 1.52-1. 45 (m, 1 H), 1. 19-1.11 (m, 1 H), 0.91 (t, J = 7.8 Hz, 3 H), 0.89 ( d, J = 7.2 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 169.41, 167.64, 137.86, 128.41, 127.76, 127.70, 73.38, 71.91, 70.89, 65.51, 51.78, 38.16, 25.09, 23.30, 15.04, 11.65;
HRMS (ESI-TOF): m / z C 18 H 27 N 2 O 2 + Calculated [M ⁺ H] + 319.2016, Found 319.2017.

N-((1S, 2S) -1-((S) -4-benzyl-4,5-dihydrooxazol-2-yl) -2- (tert-butoxy) propyl) acetamide (L80)
L80 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.29 (t, J = 7.8 Hz, 2 H), 7.22 (t, J = 7.8 Hz, 1 H), 7.18 (d, J = 7.2 Hz, 2 H), 6.31 (6.31 br, 1H, NH), 4.58 (d, J = 9.0 Hz, 1H), 4.37-4.32 (m, 1H), 4.18 (t, J = 8.4 Hz, 1H), 4.10 (dd, J = 12.0, 6.6 Hz) , 1H), 4.02 (t, J = 8.4 Hz, 1 H), 3.11 (dd, J = 13.2, 5.4 Hz, 1 H), 2.65 (dd, J = 13.8, 9.0 Hz, 1 H), 2.10 (s, 3 H) , 1.17 (d, J = 12.6 Hz, 2H), 1.13 (s, 9H);
¹³ C NMR (150 MHz, CDCl ₃ ): 170.26, 166.13, 137.18, 128.56, 126.56, 124.04, 72.44, 67.66, 66.78, 52.88, 41.84, 28.23, 23.31, 20.88;
HRMS (ESI-TOF): m / z C 19 H 29 N 2 O 3 + Calculated [M ⁺ H] + 333.2173, Found 333.2171.

N-((S) -1-((S) -4-benzyl-4,5-dihydrooxazol-2-yl) -2-phenylethyl) acetamide (L81)
L81 was prepared according to the general procedure and purified by silica gel column chromatography to give a pale yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.30-7.21 (m, 6 H), 7. 15 (d, J = 9.0 Hz, 2 H), 7.09 (d, J = 9.6 Hz, 2 H), 6.06 (br, 1 H , NH), 4.95-4.92 (m, 1H), 4.29-4.22 (m, 2H), 4.04 (dd, J = 7.8, 6.0 Hz, 1 H), 3.15 (dd, J = 13.8, 6.0 Hz, 1 H), 3.05 (dd, J = 13.8, 4.8 Hz, 1 H), 2.99 (dd, J = 13.8, 4.8 Hz, 1 H), 2.59 (dd, J = 13.8, 7.8 Hz, 1 H), 1.99 (s, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 169.35, 166.22, 137.54, 136.01, 129.48, 129.17, 128.51, 128.31, 126.91, 126.62, 72.52, 66.94, 48.43, 41.57, 37.99, 23.21;
HRMS (ESI-TOF): m / z C 20 H 23 N 2 O 2 + Calculated [M ⁺ H] + 323.1754, Found 323.1749.

N-((S) -1-((S) -4-benzyl-4,5-dihydrooxazol-2-yl) -2-methylpropyl) acetamide (L82)
L82 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, acetone-d ⁶ ): δ 7.29-7.25 (m, 4 H), 7.21-7.18 (m, 1 H), 7.13 (br, 1 H, NH), 4.52 (dd, J = 9.0, 6.0 Hz, 1 H), 4. 38-4. 33 (m, 1 H), 4. 24 (t, J = 9.0 Hz, 1 H), 3. 98 (t, J = 9.0 Hz, 1 H), 2. 92 (dd, J = 13.8, 6.0 Hz, 1 H) ), 2.70 (dd, J = 13.8, 7.2 Hz, 1 H), 2.04-1.99 (m, 1 H), 1. 95 (s, 3 H), 0.90 (t, J = 7.2 Hz, 6 H);
¹³ C NMR (150 MHz, acetone-d ⁶ ): 169.68, 169.30, 130.29, 129.08, 127.05, 72.47, 67.95, 53.06, 42.28, 32.09, 22.83, 19.40, 18.33;
HRMS (ESI-TOF): m / z C 16 H 23 N 2 O 2 + Calculated [M ⁺ H] + 275.1754, Found 275.1757.

N-((S) -1-((S) -4-benzyl-4,5-dihydrooxazol-2-yl) -2,2-dimethylpropyl) acetamide (L61)
L61 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, acetone-d ⁶ ): δ 7.29-7.26 (m, 4 H), 7.21-7.18 (m, 1 H), 7.08 (br, 1 H, NH), 4.53 (dd, J = 9.0, 2.4 Hz, 1H), 4.39-4.34 (m, 1H), 4.21 (t, J = 9.0 Hz, 1H), 3.98 (t, J = 8.4 Hz, 1H), 2.91 (dd, J = 13.8, 6.6 Hz, 1H ), 2.70 (dd, J = 13.8, 7.2 Hz, 1 H), 1.96 (s, 3 H), 0.96 (s, 9 H);
¹³ C NMR (150 MHz, acetone-d ⁶ ): δ 169.55, 166.47, 139.31, 130.30, 129.08, 127.05, 72.06, 67.98, 55.82, 42.33, 35.40, 27.00, 22.85;
HRMS (ESI-TOF): m / z C 17 H 25 N 2 O 2 + Calculated [M ⁺ H] + 289.1911, Found 289.1917.
The structure of L61 was confirmed by X-ray crystallography. The weighing parameters for the structure are freely available from the Cambridge Crystallographic Data Center under the reference number CCDC 1518967.

N-((S) -1-((R) -4-benzyl-4,5-dihydrooxazol-2-yl) -2,2-dimethylpropyl) acetamide (L83)
L83 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.30 (t, J = 7.2 Hz, 2 H), 7.23 (t, J = 7.2 Hz, 1 H), 7.20 (d, J = 7.2 Hz, 2 H), 6.03 ( br, 1 H, NH), 4.57 (d, J = 9.6 Hz, 1 H), 4.42-4. 37 (m, 1 H), 4.23 (t, J = 9.0 Hz, 1 H), 3. 97 (t, J = 8.4 Hz, 1 H) ), 3.07 (dd, J = 14.4, 5.4 Hz, 1 H), 2.66 (dd, J = 13.8, 8.4 Hz, 1 H), 2.02 (s, 3 H), 0.97 (s, 9 H);
¹³ C NMR (150 MHz, CDCl ₃ ): δ 169.40, 166.70, 137.54, 129.26, 128.56, 126.57, 71.74, 67.05, 54.88, 41.82, 35.05, 26.44, 23.39;
HRMS (ESI-TOF): m / z C 17 H 25 N 2 O 2 + Calculated [M ⁺ H] + 289.1911, Found 289.1914.

N-((S) -2,2-Dimethyl-1-((S) -4- (naphthalen-2-ylmethyl) -4,5-dihydrooxazol-2-yl) propyl) acetamide (L84)
L84 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.81 (d, J = 7.8 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 2 H), 7.62 (s, 1 H), 7.48-7.43 (m, 2 H) ), 7.32 (d, J = 8.4 Hz, 1 H), 6.06 (br, 1 H, NH), 4.58 (d, J = 9.6 Hz, 1 H), 4.54-4.44 (m, 1 H), 4.17 (t, J = 9.0 Hz, 1 H), 4.08 (t, J = 8.4 Hz, 1 H), 3.22 (dd, J = 13.8, 5.4 Hz, 1 H), 2. 80 (dd, J = 13.8, 8.4 Hz, 1 H), 2.04 (s, 3H), 0.98 (s, 9H);
¹³ C NMR (150 MHz, CDCl ₃ ): δ 169.44, 166.70, 135.18, 133.25, 128.18, 127.64, 127.51, 127.45, 126.14, 125.55, 71.79, 66.83, 55.18, 41.85, 35.04, 26.54, 23.37;
HRMS (ESI-TOF): m / z C 21 H 27 N 2 O 2 + Calculated [M ⁺ H] + 339.2067, Found 339.2068.

N-((S) -2,2-dimethyl-1-((S) -4- (naphthalen-1-ylmethyl) -4,5-dihydrooxazol-2-yl) propyl) acetamide (L85)
L85 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 8.10 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 7.8 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.55- 7.48 (m, 2H), 7.41 (t, J = 7.2 Hz, 1 H), 7.31 (d, J = 6.6 Hz, 1 H), 6.07 (br, 1 H, NH), 4.60 (d, J = 9.0 Hz, 1 H ), 4.59-4.54 (m, 1H), 4.13-4.08 (m, 2H), 3.62 (dd, J = 13.8, 5.4 Hz, 1 H), 2.95 (dd, J = 13.8, 9.6 Hz, 1 H), 2.04 ( s, 3H), 0.99 (s, 9H);
¹³ C NMR (150 MHz, CDCl ₃ ): δ 169.48, 166.76, 133.76, 131.99, 128.61, 127.07, 126.07, 126.07, 125.42, 123.73, 71.98, 66.06, 55.23, 38.93, 35.10, 26.57, 23.43;
HRMS (ESI-TOF): m / z C 21 H 27 N 2 O 2 + Calculated [M ⁺ H] + 339.2067, Found 339.2067.

N-((S) -1-((4S, 5S) -4-benzyl-5-methyl-4,5-dihydro-oxazol-2-yl) -2,2-dimethylpropyl) acetamide (L86)
L86 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.29 (t, J = 7.2 Hz, 2 H), 7.22 (t, J = 7.2 Hz, 1 H), 7.17 (d, J = 7.2 Hz, 2 H), 6.15 (6 br, 1H, NH), 4.51 (d, J = 9.0 Hz, 1H), 4.36-4.32 (m, 1H), 3.85 (dt, J = 8.4, 6.0 Hz, 1H), 3.05 (dd, J = 7.8, 5.4 Hz, 1 H), 2.59 (dd, J = 13.8, 8.4 Hz, 1 H), 2.05 (s, 3 H), 1.10 (d, J = 6.0 Hz, 3 H), 0.98 (s, 9 H);
¹³ C NMR (150 MHz, CDCl ₃ ): δ 169.42, 165.88, 137.25, 129.21, 128.49, 126.56, 80.89, 73.62, 55.06, 41.54, 35.23, 26.61, 23.40, 21.01;
HRMS (ESI-TOF): m / z C 18 H 27 N 2 O 2 + Calculated [M ⁺ H] + 303.2067, Found 303.2068.

N-((S) -1-((4S, 5S) -4-benzyl-5-isopropyl-4,5-dihydro-oxazol-2-yl) -2,2-dimethylpropyl) acetamide (L87)
L87 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.29 (tt, J = 7.2, 1.8 Hz, 2 H), 7.22 (tt, J = 7.2, 1.2 Hz, 1 H), 7.18 (dd, J = 7.2, 1.8 Hz , 2H), 6.13 (br, 1H, NH), 4.52 (d, J = 9.0 Hz, 1H), 3.98-3.62 (m, 2H), 2.97 (dd, J = 13.8, 5.4 Hz, 1H), 2.63 (2. dd, J = 13.8, 7.2 Hz, 1 H), 2.05 (s, 3 H), 1.57-1. 52 (m, 1 H), 0.99 (s, 9 H), 0.84 (d, J = 6.6 Hz, 3 H), 0.64 (d , J = 6.6 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.38, 165.95, 137.47, 129.40, 126.56, 126.71, 69.98, 55.28, 42.51, 35.01, 32.04, 26.61, 23.40, 18.06, 17.30;
HRMS (ESI-TOF): m / z C 20 H 31 N 2 O 2 + Calculated [M ⁺ H] + 331.2380, Found 331.2380.

N-((S) -1-((4S, 5S) -4-benzyl-5- (tert-butyl) -4,5-dihydrooxazol-2-yl) -2,2-dimethylpropyl) acetamide (L88) )
L88 was prepared according to the general procedure and purified by silica gel column chromatography to give a pale yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.30-7.28 (m, 2H), 7.24-7.20 (m, 3H), 5.95 (br, 1H, NH), 4.39 (d, J = 9.0 Hz, 1H) , 3.51 (dd, J = 13.8, 3.0 Hz, 1 H), 2.79 (d, J = 3.0 Hz, 1 H), 2.62 (dt, J = 9.6, 3.0 Hz, 1 H), 2.19 (dd, J = 13.8, 9.6) Hz, 1 H), 2.02 (s, 3 H), 1.08 (s, 9 H), 0.90 (s, 9 H);
¹³ C NMR (150 MHz, CDCl ₃ ) δ 181.43, 169.87, 138.43, 128.99, 128.48, 126.54, 60.98, 53.73, 41.21, 36.86, 34.01, 30.93, 26.76, 26.53, 21.21;
HRMS (ESI-TOF): m / z C 21 H 33 N 2 O 2 + Calculated [M ⁺ H] + 345.2537, Found 345.2533.

N-((S) -1-((4S, 5S) -4-benzyl-5-phenyl-4,5-dihydro-oxazol-2-yl) -2,2-dimethylpropyl) acetamide (L89)
L89 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.29-7.25 (m, 5H), 7.24-7.21 (m, 1H), 7.20-7.18 (m, 2H), 6.98-6.96 (m, 2H), 6.09 (m, 2H) br, 1H, NH), 5.11 (d, J = 7.2 Hz, 1 H), 4.67 (d, J = 9.6 Hz, 1 H), 4.30 (dt, J = 7.8, 6.0 Hz, 1 H), 3.16 (dd, J = 13.8, 6.0 Hz, 1 H), 2.81 (dd, J = 13.8, 7.8 Hz, 1 H), 2.07 (s, 3 H), 1.03 (s, 9 H);
¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.47, 165.52, 140.10, 129.61, 128.66, 128.51, 128.23, 126.70, 125.83, 85.88, 75.39, 55.47, 41.91, 35.09, 26.92, 23.39;
HRMS (ESI-TOF): m / z C 23 H 29 N 2 O 2 + Calculated [M ⁺ H] + 365.2224, Found 365.2222.

N-((S) -1-((4S, 5S) -4-benzyl-5- (4- (trifluoromethyl) -phenyl) -4,5-dihydrooxazol-2-yl) -2,2- Dimethylpropyl) acetamide (L90)
L90 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.49 (d, J = 8.4 Hz, 2 H), 7.32-7.29 (m, 2 H), 7.27-7.24 (m, 1 H), 7.20-7.18 (m, 2 H) , 6.96 (d, J = 7.8 Hz, 2 H), 6.05 (br, 1 H, NH), 5. 16 (d, J = 7.2 Hz, 1 H), 4.69 (d, J = 9.6 Hz, 1 H), 4.26 (ddd, J = 9.0, 7.2, 5.4 Hz, 1 H), 3.27 (dd, J = 13.8, 5.4 Hz, 1 H), 2. 76 (dd, J = 13.8, 9.0 Hz, 1 H), 2.08 (s, 3 H), 1.05 (s , 9H);
¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.49, 165.46, 144.15, 136.65, 130.27 (q, J = 32.9 Hz), 129.58, 128.70, 126.94, 125.74, 125.59 (q, J = 3.3 Hz), 123.85 (q , J = 271.2 Hz), 84.81, 75.94, 55.45, 42.03, 34.98, 26.71, 23.37;
¹⁹ F NMR (376 MHz, CDCl ₃ ): δ -62.94 (s, 3F);
HRMS (ESI-TOF): m / z C 24 H 28 F 3 N 2 O 2 + Calculated [M ⁺ H] + 433.2097, Found 433.2097.

N-((S) -1-((4S, 5S) -5-([1,1'-biphenyl] -4-yl) -4-benzyl-4,5-dihydrooxazol-2-yl) -2 , 2-Dimethylpropyl) acetamide (L91)
L91 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.55-7.53 (m, 2 H), 7.49 (dt, J = 8.4, 1.8 Hz, 2 H), 7.44-7.41 (m, 2 H), 7.35-7.33 (m, 2) 1H), 7.31-7.28 (m, 2H), 7.25-7.21 (m, 3H), 7.03-7.02 (m, 2H), 6.13 (br, 1H, NH), 5.16 (d, J = 7.2 Hz, 1H) , 4.69 (d, J = 10.2 Hz, 1 H), 4. 35 (ddd, J = 7.8, 7.2, 6.0 Hz, 1 H), 3.20 (dd, J = 13.8, 6.0 Hz, 1 H), 2.82 (dd, J = 13.8 , 7.8 Hz, 1 H), 2.08 (s, 3 H), 1.05 (s, 9 H);
¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.47, 165.56, 141.40, 139.05, 137.00, 129.78, 128.48, 127.48, 127.36, 127.02, 126.73, 126.18, 85.63, 75.41, 55.48, 41.93, 35.10. , 23.39;
HRMS (ESI-TOF): m / z C 29 H 33 N 2 O 2 + Calculated [M ⁺ H] + 441.2537, Found 441.2534.

N-((S) -1-((4S, 5S) -4-benzyl-5- (2,4,6-triisopropyl-phenyl) -4,5-dihydrooxazol-2-yl) -2,2 -Dimethylpropyl) -acetamide (L92)
L92 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.17-7.15 (m, 2H), 7.12-7.09 (m, 2H), 7.01-6.99 (m, 3H), 6.38 ((br, 1H, NH), 5.92 (d, J = 9.0 Hz, 1 H), 5.64 (d, J = 11.4 Hz, 1 H), 5.00-4.94 (m, 1 H), 4.22 (d, J = 9.6 Hz, 1 H), 3. 85 (sep, J = 6.6 Hz, 1 H), 3.30 (sep, J = 6.6 Hz, 1 H), 2. 88 (sep, J = 6.6 Hz, 1 H), 2.59 (dd, J = 13.8, 3.6 Hz, 1 H), 2.50 (dd, J = 14.4, 11.4 Hz, 1 H), 1. 92 (s, 3 H), 1. 38 (d, J = 7.2 Hz, 3 H), 1. 36 (d, J = 6.6 Hz, 3 H), 1. 29 (d, J = 6.0 Hz, 3 H) , 1.27-1.25 (m, 9 H), 0.99 (s, 9 H);
¹³ C NMR (151 MHz, CDCl ₃ ) δ 170.65, 169.51, 149.21, 146.48, 129.31, 129.12, 128.32, 126.21, 121.07, 60.77, 60.02, 55.98, 38.68, 34.52, 34.09, 30.01, 29.54, 26.49 , 25.10, 24.99, 24.37, 23.86, 23.85, 23.38, 23.11;
HRMS (ESI-TOF): m / z C 32 H 47 N 2 O 2 + Calculated [M ⁺ H] + 491.3632, Found 491.3634.

N-((S) -1-((4S, 5S) -4-benzyl-5- (3,5-di-tert-butylphenyl) -4,5-dihydrooxazol-2-yl) -2,2 -Dimethylpropyl) acetamide (L93)
L93 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.31-7.29 (m, 3H), 7.24-7.21 (m, 3H), 6.78 (d, J = 1.8 Hz, 2H), 6.15 ((br, 1H, NH) ), 5.16 (d, J = 6.6 Hz, 1 H), 4.69 (d, J = 9.6 Hz, 1 H), 4.31-4.27 (m, 1 H), 3.20 (dd, J = 13.8, 6.0 Hz, 1 H), 2.76 (dd, J = 13.2, 8.4 Hz, 1 H), 2.07 (s, 3 H), 1.22 (s, 18 H), 1.06 (s, 9 H);
¹³ C NMR (151 MHz, CDCl ₃ ) δ 169.34, 165.70, 151.12, 137.18, 129.67, 128.59, 126.15, 119.70, 86.51, 75.66, 55.43, 42.49, 35.30, 34.80, 31.34, 26.77, 23.43;
HRMS (ESI-TOF): m / z C 31 H 45 N 2 O 2 + Calculated [M ⁺ H] + 477.3476, Found 477.3475.

N-((S) -1-((S) -4-benzyl-4,5-dihydrooxazol-2-yl) -2,2-dimethylpropyl) -2,6-difluorobenzamide (L94)
L94 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.40-7.35 (m, 1H), 7.29-7.27 (m, 2H), 7.23-7.18 (m, 3H), 6.98-6.94 (m, 2H), 6.62 (6.62 (m, 2H) br, 1 H, NH), 4. 78 (d, J = 9.6 Hz, 1 H), 4.41-4. 37 (m, 1 H), 4. 20 (t, J = 9.0 Hz, 1 H), 4.07 (dd, J = 9.0, 6.6 Hz , 1H), 3.04 (dd, J = 13.8, 5.4 Hz, 1 H), 2.67 (dd, J = 13.8, 8.4 Hz, 1 H), 1.05 (s, 9 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 166.12, 159.98 (dd, J = 250.5, 6.5 Hz), 159.72, 137.51, 131.67 (t, J = 9.9 Hz), 129.27, 128.51, 126.57, 114.42 (t, J = 19.7 Hz), 111.97 (dd, J = 20.7, 3.2 Hz), 71.82, 66.89, 55.66, 41.55, 35.54, 26.53;
¹⁹ F NMR (376 MHz, CDCl ₃ ): δ -112.16 (s, 2F);
HRMS (ESI-TOF): m / z C 22 H 25 F 2 N 2 O 2 + Calculated [M ⁺ H] + 387.1879, Found 387.1879.

N-((S) -1-((S) -4-benzyl-4,5-dihydrooxazol-2-yl) -2-methylpropyl) -2,6-difluorobenzamide (L95)
L95 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.40-7.35 (m, 1H), 7.30-7.26 (m, 2H), 7.23-7.18 (m, 3H), 6.98-6.94 (m, 2H), 6.62 (6.62 (m, 2H) Br, 1 H, NH), 4. 84 (dd, J = 9.0, 4.8 Hz, 1 H), 4.41-4.36 (m, 1 H), 4.25 (t, J = 9.0 Hz, 1 H), 4.08 (dd, J = 9.0, 7.2 Hz, 1 H), 3.01 (dd, J = 13.8, 5.4 Hz, 1 H), 2.71 (dd, J = 13.8, 7.8 Hz, 1 H), 2.27-2.20 (m, 1 H), 1.03 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 7.2 Hz, 3H);
¹³ C NMR (150 MHz, CDCl ₃ ): 166.28, 160.01 (dd, J = 250.5, 6.5 Hz), 159.86, 137.45, 131.67 (t, J = 11.0 Hz), 129.35, 128.48, 126.59, 114.33 (t, J = 20.7 Hz), 111.97 (dd, J = 21.8, 4.4 Hz), 72.35, 66.83, 52.85, 41.60, 31.67, 18.77, 17.59;
¹⁹ F NMR (376 MHz, CDCl ₃ ): δ -112.24 (s, 2F);
HRMS (ESI-TOF): m / z C 21 H 23 F 2 N 2 O 2 + Calculated [M ⁺ H] + 373.1722, Found 373.1726.

N-((S) -1-((S) -4-benzyl-4,5-dihydrooxazol-2-yl) -2-methylpropyl) -2,4,6-trifluorobenzamide (L96)
L96 was prepared according to the general procedure and purified by silica gel column chromatography to give a pale yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.30-7.27 (m, 2H), 7.23-7.20 (m, 1H), 7.19-7.18 (m, 2H), 6.75-6.71 (m, 2H), 6.62 (6.62 (m, 2H) Br, 1 H, NH), 4.81 (dd, J = 9.0, 4.8 Hz, 1 H), 4.40-4.38 (m, 1 H), 4.26 (t, J = 9.0 Hz, 1 H), 4.08 (dd, J = 8.4, 7.2 Hz, 1 H), 3.01 (dd, J = 13. 8, 6.0 Hz, 1 H), 2. 70 (dd, J = 14.4, 7.2 Hz, 1 H), 2.27-2.19 (m, 1 H), 1.02 (d, J = 7.2 Hz, 3H), 0.95 (d, J = 7.2 Hz, 3H);
¹³ C NMR (150 MHz, CDCl ₃ ): 166.23, 163.44 (dt, J = 251.6, 15.3 Hz), 160.59 (ddd, J = 252.6, 15.3, 9.8 Hz), 159.04, 137.40, 129.30, 128.48, 126.60, 111.00 (dt, J = 20.7, 4.4 Hz), 100.94 (tt, J = 25.2, 2.3 Hz), 72.40, 66.80, 52.91, 41.58, 31.60, 18.74, 17.55;
¹⁹ F NMR (376 MHz, CDCl ₃ ): δ -104.17 (t, J = 8.6 Hz, 1 F), -108.79 (d, J = 7.1 Hz, 2 F);
HRMS (ESI-TOF): m / z C 21 H 22 F 3 N 2 O 2 + Calculated [M ⁺ H] + 391.1628, Found 391.1628.

N-((S) -1-((S) -4-benzyl-4,5-dihydrooxazol-2-yl) -2-methylpropyl) -2,3,4,5,6-pentafluorobenzamide ( L97)
L97 was prepared according to the general procedure and purified by silica gel column chromatography to give a pale yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.31-7.28 (m, 2 H), 7.24-7.21 (m, 1 H), 7.19-7.18 (m, 2 H), 6.70 (br, 1 H, NH), 4.79 (4 dd, J = 9.0, 4.8 Hz, 1 H), 4.42-4. 37 (m, 1 H), 4. 29 (t, J = 9.0 Hz, 1 H), 4.09 (dd, J = 9.0, 7.2 Hz, 1 H), 2.99 (dd , J = 13.8, 6.0 Hz, 1 H), 2.72 (dd, J = 13.8, 7.8 Hz, 1 H), 2.28-2.20 (m, 1 H), 1.01 (d, J = 7.2 Hz, 3 H), 0.94 (d, J = 7.2 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 165.97, 156.90, 137.34, 129.29, 128.51, 126.67, 72.66, 66.77, 53.26, 41.61, 31.55, 18.72, 17.47;
¹⁹ F NMR (376 MHz, CDCl ₃ ): δ -140.41-140.49 (m, 2F), -150.99 (t, J = 20.7 Hz, 1F), -160.22--160.37 (m, 2F);
HRMS (ESI-TOF): m / z C 21 H 20 F 5 N 2 O 2 + Calculated [M ⁺ H] + 427.1439, Found 427.1439.

N-((1S, 2S) -1-((S) -4-benzyl-4,5-dihydrooxazol-2-yl) -2-methylbutyl) -2,6-difluorobenzamide (L98)
L98 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.40-7.35 (m, 1H), 7.30-7.27 (m, 2H), 7.23-7.18 (m, 3H), 6.98-6.94 (m, 2H), 6.68 (6, 7) Br, 1H, NH), 4.87 (dd, J = 8.4, 4.8 Hz, 1H), 4.41-4.36 (m, 1H), 4.25 (t, J = 9.0 Hz, 1H), 4.07 (dd, J = 9.0, 4.8 Hz, 1 H), 3.01 (dd, J = 13.8, 7.8 Hz, 1 H), 2.70 (dd, J = 13.8, 7.8 Hz, 1 H), 2.03-1.97 (m, 1 H), 1.57-1. 51 (m, 1 H) ), 1.25-1.18 (m, 1 H), 0.98 (d, J = 6.6 Hz, 3 H), 0.95 (t, J = 7.8 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 166.20, 160.04 (dd, J = 251.6, 6.5 Hz), 159.69, 137.46, 131.66 (t, J = 11.0 Hz), 129.34, 128.48, 126.59, 114.30 (t, J = 19.8 Hz), 111.97 (dd, J = 21.8, 4.4 Hz), 72.31, 66.79, 52.27, 41.58, 38.21, 25.00, 15.15, 11.68;
¹⁹ F NMR (376 MHz, CDCl ₃ ): δ -112.27 (s, 2F);
HRMS (ESI-TOF): m / z C 22 H 25 F 2 N 2 O 2 + Calculated [M ⁺ H] + 387.1879, Found 387.1872.

N-((1S, 2S) -1-((S) -4-benzyl-4,5-dihydrooxazol-2-yl) -2-methylbutyl) -2,4,6-triisopropylbenzamide (L99)
L99 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.30-7.28 (m, 2H), 7.23-7.20 (m, 1H), 7.19-7.18 (m, 2H), 7.01 (s, 2H), 6.35 (br, 6) 1H, NH), 4.91 (dd, J = 8.4, 4.8 Hz, 1 H), 4.40-4.34 (m, 1 H), 4.18 (t, J = 8.4 Hz, 1 H), 4.03 (dd, J = 8.4, 7.2 Hz , 1H), 3.10 (dd, J = 13.8, 5.4 Hz, 1H), 3.06-3.02 (m, 2H), 2.91-2.86 (m, 1H), 2.56 (dd, J = 13.8, 8.4 Hz, 1H), 2.01-1.94 (m, 1 H), 1.59-1.52 (m, 1 H), 1.29-1 .19 (m, 19 H), 0.98-0. 95 (m, 6 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 170.03, 166.31, 149.72, 145.93, 134.68, 129.10, 128.59, 126.58, 121.04, 120.87, 72.09, 67.02, 51.97, 41.67, 38.25, 34.39, 30.91, 0.75 , 25.35, 24.78, 24.40, 23.98, 23.96, 15.29, 11.74;
HRMS (ESI-TOF): m / z C 31 H 45 N 2 O 2 + Calculated [M ⁺ H] + 477.3476, Found 477.3479.

N-((1S, 2S) -1-((S) -4- (2,6-difluorobenzyl) -4,5-dihydrooxazol-2-yl) -2-methylbutyl) -2,6-difluorobenzamide (L100)
L100 was prepared according to the general procedure and purified by silica gel column chromatography to give a white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.39-7.34 (m, 1H), 7.20-7.15 (m, 1H), 6.97-6.93 (m, 2H), 6.87-6.82 (m, 2H), 6.68 (m, 2H) Br, 1 H, NH), 4. 88 (dd, J = 8.4, 4.8 Hz, 1 H), 4.44-4. 39 (m, 1 H), 4. 27 (t, J = 9.0 Hz, 1 H), 4. 14 (dd, J = 9.0, 7.2 Hz, 1 H), 3.00 (dd, J = 13.8, 6.0 Hz, 1 H), 2.83 (dd, J = 13.8, 7.8 Hz, 1 H), 2.05-1.98 (m, 1 H), 1.58- 51 (m, 1 H) ), 1.27-1.19 (m, 1 H), 0.98 (d, J = 6.6 Hz, 3 H), 0.96 (t, J = 7.2 Hz, 3 H);
¹³ C NMR (150 MHz, CDCl ₃ ): 166.42, 161.67 (dd, J = 245.1, 7.7 Hz), 160.07 (dd, J = 251.6, 6.6 Hz), 159.63, 131.63 (t, J = 9.9 Hz), 128.34 (t, J = 9.9 Hz), 114. 28 (t, J = 19.7 Hz), 113. 45 (t, J = 20.7 Hz), 111.94 (dd, J = 20.7, 3.3 Hz), 111. 17 (dd, J = 20.7, 4.4 Hz), 72.51, 65.30, 52.28, 38.27, 28.31, 25.07, 15.05, 11.68;
¹⁹ F NMR (376 MHz, CDCl ₃ ): δ -112.13 (s, 2F), -114.28 (s, 2F);
HRMS (ESI-TOF): m / z C 22 H 23 F 4 N 2 O 2 + Calculated [M ⁺ H] + 423.1690, Found 423.1698.

Optimization of reaction conditions Screening of Pd source for arylation of isobutyric acid amide ^{*, ``}

^* Conditions: 1,2.0 equivalents of 4-iodo toluene 0.1 mmol, 10 mol% of Pd, the 10mol% L22,2.0 equivalents of Ag ₂ CO _3, toluene 0.5mL, 80 ℃, 48 hours. The ratio of ^† yield and 4b / 4b 'is determined by ¹ H NMR analysis of the crude product using CH ₂ Br ₂ as an internal standard, enantiomeric ratio (er) was determined by chiral high performance liquid chromatography.
Screening of oxidants for arylation of isobutyric acid amides ^{*, †}

^* Conditions: 1,2.0 equivalents of 4-iodotoluene, 10 mol% of _{Pd (MeCN) 2 Cl 2,} 10mol% of L82,2.0 equivalents of oxidant 0.1 mmol, 0.5 mL of toluene, 80 ° C., 48 hours. The ratio of ^† yield and 4b / 4b 'is determined by ¹ H NMR analysis of the crude product using CH ₂ Br ₂ as an internal standard, enantiomeric ratio (er) was determined by chiral high performance liquid chromatography.
Screening of Bases for Arylation of Isobutyric Acid Amide ^{*, †}

^* Conditions: 3,2.0 equivalents of 4-iodo toluene 0.1 mmol, 10 mol% of _{Pd (MeCN) 2 Cl 2,} 10mol% of L82,2.0 equivalents of Ag ₂ CO _3, 2.0 equivalent of base, 0.5 mL of toluene, 80 ° C, 48 hours. The ratio of ^† yield and 4b / 4b 'is determined by ¹ H NMR analysis of the crude product using CH ₂ Br ₂ as an internal standard, enantiomeric ratio (er) was determined by chiral high performance liquid chromatography. ^The reaction temperature was 60 ° C. Using ^§ 20mol% of L82. ^|| N ₂ reaction under.
Preliminary screening of ligands for the arylation of isobutyric acid amides ^{*, †}

^* Conditions: 3,2.0 equivalents of 4-iodo toluene 0.1 mmol, 10 mol% of _{Pd (MeCN) 2 Cl 2,} 20mol% of the ligand, 2.0 eq of Ag ₂ CO _3, 2.0 equivalent of NaTFA, of 0.5mL Toluene, 60 ° C., N ₂ , 48 hours. The ratio of ^† yield and 4b / 4b 'is determined by ¹ H NMR analysis of the crude product using CH ₂ Br ₂ as an internal standard, enantiomeric ratio (er) was determined by chiral high performance liquid chromatography.
Further screening of ligands for the arylation of isobutyric acid amides ^{*, †}

^* Conditions: 0.1 mmol of ₃ , 2.0 equivalents of iodotoluene, 10 mol% of Pd (MeCN) ₂ Cl ₂ , 20 mol% of ligands, 2.0 equivalents of Ag ₂ CO ₃ , 2.0 equivalents of NaTFA, 0.5 mL of toluene, 60 ° C., N ₂ , 48 hours.
The ratio of ^† yield and 4b / 4b 'is determined by ¹ H NMR analysis of the crude product using CH ₂ Br ₂ as an internal standard, enantiomeric ratio (er) was determined by chiral high performance liquid chromatography. ^‡ 3.0 equivalents of 4-iodotoluene were used. Toluene was used in ^§ 0.25mL. ^The reaction time was 72 hours. Isolated yield of ^paragraph 4b.

General Procedure for Pd (II) -Catalyzed Arylation of Isobutyric Acid Amides Method A

The reaction tube equipped with a magnetic stir bar (10 mL) to the amide 3 (0.1 mmol), aryl iodide (0.30mmol), Pd (MeCN) 2 Cl 2 (0.01mmol, 2.6mg), L61 (0.02mmol, 5.8mg ), Ag ₂ CO ₃ (0.20 mmol, 55.2 mg), NaTFA (0.2 mmol, 27.2 mg). The reaction tube was evacuated and backfilled with nitrogen (x 3). To the tube was added toluene (0.25 mL) and the tube was sealed and heated to 60 ° C. for 72 hours. The crude reaction mixture was filtered through Celite® and washed with EtOAc. The solvent was removed under reduced pressure and the residue was purified by preparative TLC to give the desired product.
Method B

In a reaction tube (10 mL) equipped with a magnetic stirrer bar, amide 3 (0.1 mmol), aryl iodide (0.30 mmol), Pd (OAc) ₂ (0.01 mmol, 2.3 mg), L89 (0.02 mmol, 7.3 mg), Ag ₂ CO ₃ (0.20 mmol, 55.2 mg) was charged. To the tube was added toluene (0.25 mL) and the tube was sealed and heated to 50 ° C. for 72 hours. The crude reaction mixture was filtered through Celite® and washed with EtOAc. The solvent was removed under reduced pressure and the residue was purified by preparative TLC to give the desired product.
Gram-scale arylation of isobutyric acid amide

Magnetic stir bar and the reaction tube equipped (50 mL) to the amide 3 (5.0mmol, 1.5g), iodobenzene (15.0mmol, 3.0g), Pd ( MeCN) 2 Cl 2 (0.5mmol, 128.9mg), L61 ( _{0.6mmol, 172.9mg), Ag 2 CO} 3 (10.0mmol, 2.8g), packed NaTFA (10.0mmol, 1.2g). The reaction tube was evacuated and backfilled with nitrogen (x 3). Toluene (12.5 mL) was added to the tube and the tube was sealed and heated to 60 ° C. for 96 hours. The crude reaction mixture was filtered through Celite® and washed with EtOAc. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give the desired product as white solid in 65% yield (1.2 g).

Pd (II) catalyzed arylation of quaternary amino acids Optimization of reaction conditions Initial optimization of Pd (II) catalyzed arylation of quaternary amino acids ^*,,

^* Conditions: 0.1 mmol of 3, x equivalent of p-Tol-I, 10 mol% of Pd, 20 mol% of L82, y equivalent of oxidant, 0.25 mL of solvent, 60 ° C., 72 hours. The ratio of ^† yield and 6b / 6b 'is determined by ¹ H NMR analysis of the crude product using CH ₂ Br ₂ as an internal standard, enantiomeric ratio (er) was determined by chiral high performance liquid chromatography.
Ligand Screening for Pd (II) -Catalyzed Arylation of Quaternary Amino Acids ^{*, †}

^* Conditions: 0.2 mmol 5, 3.0 equivalents p-Tol-I, 10 mol% Pd (OAc) ₂ , 20 mol% ligand, 2.0 equivalents AgOAc, 72 hours. The ratio of ^† yield and 6b / 6b 'is determined by ¹ H NMR analysis of the crude product using CH ₂ Br ₂ as an internal standard, enantiomeric ratio (er) was determined by chiral high performance liquid chromatography. Isolated yield of ^‡ mono product 6b.
General Procedure for Pd (II) -Catalyzed Arylation of Quaternary Amino Acids

In a reaction tube (10 mL) equipped with a magnetic stirrer bar, 5 (0.2 mmol), aryl iodide (0.60 mmol), Pd (OAc) ₂ (0.02 mmol, 4.5 mg), L100 (0.04 mmol, 16.9 mg), AgOAc (0.40 mmol, 66.8 mg) was loaded. To the tube was added 1,1,1,3,3,3-hexafluoro-2-propanol (0.25 mL) and the tube was sealed and heated to 35 ° C. for 72 hours. The crude reaction mixture was filtered through Celite® and washed with EtOAc. The solvent was removed under reduced pressure and the residue was purified by preparative TLC to give the desired product.

N-((1S, 2S) -1-((R) -4-isobutyl-4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide [(S, R) -L101]
¹ H NMR (600 MHz, CDCl ₃ ) δ 6.22 (d, J = 7.8 Hz, 1 H), 4.66-4.63 (m, 1 H), 4.38-4.35 (m, 1 H), 4.14-4.09 (m, 1 H), 3.86-3.84 (m, 1H), 2.02 (s, 3H), 1.89-1.82 (m, 1H), 1.76-1.69 (m, 1H), 1.60-1.56 (m, 1H), 1.53-1.47 (m, 1H) ), 1.29-1 .24 (m, 1 H), 1.20-1.13 (m, 1 H), 0.95-0.92 (m, 9 H), 0.90 (d, J = 7.2 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃₎ ) HRMS (ESI-TOF) C ₁₄ H ₂₇ N ₂ O ₂ ⁺ calculated value [M,) 169.4, 166.1, 73.4, 64. 5, 45.7, 38.2, 25.2, 25.3, 22.9, 22.5, 14.9, 11.7; + H] ⁺ : 255.2067; Found: 255.2068.

N-((1S, 2S) -1-((S) -4-isobutyl-4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide [(S, S) -L101]
¹ H NMR (600 MHz, CDCl ₃ ) δ 6.66 (d, J = 8.4 Hz, 1 H), 4.68-4.65 (m, 1 H), 4.33-4.30 (m, 1 H), 4.10-4.04 (m, 1 H), 3.85-3.83 (m, 1H), 1.97 (s, 3H), 1.86-1.78 (m, 1H), 1.70-1.63 (m, 1H), 1.57-1.52 (m, 1H), 1.47-1.40 (m, 1H) ), 1.28 to 1.23 (m, 1 H), 1.16 to 1.08 (m, 1 H), 0.92 to 0.83 (m, 12 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.6, 166.3, 73.3, 641, 1, 51.7, HRMS (ESI-TOF) Calcd for C ₁₄ H ₂₇ N ₂ O ₂ ⁺ [M + H] ⁺ : 255.2067; found: 255.2066. 45.4, 38.0, 25.3, 25.0, 23.2, 22.4, 15.1, 11.6;

N-((S) -1-((R) -4-isobutyl-4,5-dihydrooxazol-2-yl) -2,2-dimethylpropyl) acetamide [(S, R) -L102]
¹ H NMR (600 MHz, CDCl ₃ ) δ 6.13 (d, J = 9.6 Hz, 1 H), 4.56-4. 54 (m, 1 H), 4.36-4. 33 (m, 1 H), 4.16-4. 10 (m, 1 H), 3.83-3.81 (m, 1H), 2.03 (s, 3H), 1.75-1.68 (m, 1H), 1.60-1.55 (m, 1H), 1.29-1.25 (m, 1H), 0.98 (s, 9H), 0.95 (d, J = 6.6 Hz, 3 H), 0.93 (d, J = 6.6 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.4, 166.0, 73.1, 64.3, 54.8, 45.8, 35.1, 26.4 , 25.4, 23.4, 22.9, 22.5 ; HRMS (ESI-TOF) C 14 H 27 N 2 O 2 + calculated ^{[M + H] +: 255.2067} ; Found: 255.2067.

N-((S) -1-((R) -4-isobutyl-4,5-dihydrooxazol-2-yl) -2-phenylethyl) acetamide [(S, R) -L103]
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.28-7.25 (m, 2H), 7.25-7.21 (m, 1H), 711-7.08 (m, 2H), 6.17 (d, J = 7.2 Hz, 1H), 4.93-4.90 (m, 1H), 4.40-4.37 (m, 1H), 4.08-4.03 (m, 1H), 3.87-3.84 (m, 1H), 3.18 (dd, J 1 = 13.8 Hz, J 2 = 6.0 Hz, 1 H), 3.07 (dd, J ₁ = 13. 8 Hz, J ₂ = 4.8 Hz, 1 H), 2.00 (s, 3 H), 1.64-1. 57 (m, 1 H), 1. 38-1.34 (m, 1 H), 1. 14 -1.09 (m, 1 H), 0.89 (d, J = 6.6 Hz, 3 H), 0.85 (d, J = 6.6 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.3, 165.4, 136.0, 129.7 , 128.2, 126.8, 73.8, 64.1, 48.3, 45.4, 37.8, 25.2, 23.2, 22.60, 22.58; HRMS (ESI-TOF) C ₁₇ H ₂₅ N ₂ O ₂ ⁺ calculated value [M + H] ⁺ : 289.1910; Found: 289.1910.

N-((1S, 2S) -1-((R) -4-isopropyl-4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide [(S, R) -L104]
¹ H NMR (600 MHz, CDCl ₃ ) δ 6.18 (d, J = 8.4 Hz, 1 H), 4.65-4.63 (m, 1 H), 4.28 (dd, J ₁ = 9.6 Hz, J ₂ = 8.4 Hz, 1 H) , 3.99-3.96 (m, 1H), 3.93-3.89 (m, 1H), 2.02 (s, 3H), 1.88-1.82 (m, 1H), 1.78-1.73 (m, 1H), 1.55-1.49 (m, 1H) 1 H), 1.20-1. 13 (m, 1 H), 0.96 (d, J = 7.2 Hz, 3 H), 0.94-0.88 (m, 9 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.3, 166.1, 71.7, HRMS (ESI-TOF) C ₁₃ H ₂₅ N ₂ O ₂ ⁺ calculated value [M + H] ⁺ : 241.1911; actual value: 70.3, 51.7, 38.2, 32.4, 25.3, 18.9, 18.1, 11.7; 241.1911.

N-((1S, 2S) -1-((R) -4-benzyl-4,5-dihydrooxazol-2-yl) -2-methylbutyl) acetamide [(S, R) -L105]
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.32-7.29 (m, 2 H), 7.24-7.22 (m, 1 H), 7.20-7.17 (m, 2 H), 6.15 (d, J = 8.4 Hz, 1 H), 4.67-4.65 (m, 1H), 4.42-4.37 (m, 1H), 4.25-4.22 (m, 1H), 4.02-3.99 (m, 1H), 3.09 (dd, J 1 = 13.8 Hz, J 2 = 4.8 Hz, 1H), 2.65 (dd , J 1 = 13.8 Hz, J 2 = 9.0 Hz, 1H), 2.02 (s, 3H), 1.87-1.81 (m, 1H), 1.51-1.44 (m, 1H), 1.19 -1.11 (m, 1 H), 0.92 (t, J = 7.5 Hz, 3 H), 0.89 (d, J = 7.2 Hz, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.4, 166.9, 137.5, 129.2 , 128.5, 126.6, 72.2, 66.8, 51.6, 41.7, 38.2, 25.1, 23.3, 15.0, 11.7; HRMS (ESI-TOF) C ₁₇ H ₂₅ N ₂ O ₂ ⁺ calculated value [M + H] ⁺ : 289.1910; Found: 289.1911.

(R) -N-((4-Benzyl-4,5-dihydrooxazol-2-yl) methyl) -acetamide [(R) -L64]
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.32-7.30 (m, 2 H), 7.25-7.22 (m, 1 H), 7.20-7.18 (m, 2 H), 6.39 (br s, 1 H), 4.43-4. 37 ( m, 1H), 4.27 (t , J = 9.0 Hz, 1H), 4.06-4.01 (m, 3H), 3.07 (dd, J 1 = 13.8 Hz, J 2 = 6.0 Hz, 1H), 2.68 (dd, J ₁ = 13.8 Hz, J ₂ = 8.1 Hz, 1 H), 2.03 (s, 3 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.1, 164.7, 137.4, 129.1, 128.5, 126.6, 72.6, 66.8, 41.5, 37.0, 22.9; HRMS (ESI- TOF) C 13 H 17 N 2 O 2 + calculated ^{[M + H] +: 233.1285} ; Found: 233.1285.

N-((1S, 2S) -1- (4,5-dihydrooxazol-2-yl) -2-methylbutyl) -acetamide [(S) -L106]
¹ H NMR (600 MHz, CDCl ₃ ) δ 6.43 (d, J = 8.4 Hz, 1 H), 4.73-4.69 (m, 1 H), 4.35-4.27 (m, 2 H), 3.86-3. 82 (m, 2 H), 2.01 (s, 3 H), 1.90-1. 83 (m, 1 H), 1.52-1. 45 (m, 1 H), 1.20-1. ¹³ (m, 1 H), 0.94-0.90 (m, 6 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.6, 167.8, 68.0, 53.6, 51.7, 38.1, 25.1, 23.2, 15.2, 11.7; HRMS (ESI-TOF) C ₁₀ H ₁₉ N ₂ O ₂ ⁺ calculated value [M + H] ⁺ : 199.1441 Found: 199.1441.

N-((S) -2,2-Dimethyl-1-((S) -4- (4- (trifluoromethyl) -benzyl) -4,5-dihydrooxazol-2-yl) propyl) acetamide [( S, S) -L107]
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.56-7.55 (m, 2 H), 7.32-7.30 (m, 2 H), 6.03 (d, J = 9.6 Hz, 1 H), 4.56 (d, J = 9.6 Hz, 1H), 4.40-4.34 (m, 1H ), 4.23-4.20 (m, 1H), 4.00 (dd, J 1 = 9.0 Hz, J 2 = 7.2 Hz, 1H), 3.04 (dd, J 1 = 13.8 Hz, J ₂ = 6.0 Hz, 1 H), 2. 74 (dd, J ₁ = 13. 8 Hz, J ₂ = 7.8 Hz, 1 H), 2.05 (s, 3 H), 0.97 (s, 9 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.4, 166.9, 141.9, 129.5, 129.0 (q, J _FC = 32.2 Hz), 125.4 (q, J _FC = 3.6 Hz), 124.2 (q, J _FC = 270.2 Hz), 71.7, 66.6, 55.2, 41.6, 34.9, 26.5, 23.4; HRMS (ESI-TOF) C 17 H 25 N 2 O 2 + calculated ^{[M + H] +: 357.1784} ; Found: 357.1787.

N-((S) -1-((4S, 5S) -4-benzyl-5- (4- (trifluoromethyl) -phenyl) -4,5-dihydrooxazol-2-yl) -2,2- Dimethylpropyl) -acetamide [(S, S, S) -L108]
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.49 (d, J = 7.8 Hz, 2 H), 7.31-7.29 (m, 2 H), 7.26-7.24 (m, 1 H), 7.20-7.18 (m, 2 H), 6.97 (d, J = 7.8 Hz, 2 H), 6.17 (br s, 1 H), 5.17 (d, J = 7.2 Hz, 1 H), 4.70 (d, J = 9.6 Hz, 1 H), 4.28-4.25 (m, 1H), 3.26 (dd, J 1 = 13.8 Hz, J 2 = 5.4 Hz, 1H), 2.76 (dd, J 1 = 13.8 Hz, J 2 = 9.0 Hz, 1H), 2.08 (s, 3H), 1.05 ( s, 9H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 169.5, 165.4, 144.1, 136.6, 130.2 (q, J _FC = 32.0 Hz), 129.5, 128.6, 126.9, 125.7, 125.5 (q, J _FC = 3.5 Hz), 123.8 (q, J _FC = 270.5 Hz), 84.7, 75.9, 55.4, 42.0, 36.7, 26.7, 23.3; HRMS (ESI-TOF) C ₂₄ H ₂₈ F ₃ N ₂ O ₂ ⁺ calculated value [ M + H] ⁺ : 433.3097; found: 433.2098.

The patents, patent applications and articles cited herein are each incorporated by reference.
The foregoing description and examples are for the purpose of illustration and are not to be construed as limiting. Still other variations within the spirit and scope of the present invention are possible and will readily occur to those skilled in the art.

Claims (36)

Structure is the following formula A,
(In the formula:
R ³ is a C ₁ -C ₄ alkyl group or a fluoro-substituted benzoyl group;
The depicted cyclic moiety (ring) wherein R ⁵ and R ⁶ may be substituents is a cyclic ring structure comprising one fused ring or two fused rings each containing 5 or 6 atoms in the ring;
Z is oxygen (O) or CH when part of a double bond;
R ⁵ and R ⁶ are the same or different and are hydride, halogen other than iodo, linear, branched and cyclic C ₁ -C ₇ hydrocarbyl, C ₁ -C ₇ hydrocarbyloxy, carboxy C ₁ -C ₆ hydrocarbyl, trifluoromethyl, C ₁ -C ₆ hydrocarbyl Boyle, nitro, C ₁ -C ₆ hydrocarbylthio oxy, and cyano group, or from the group consisting of benzyl group whose ring is substituted with 1-5 fluoro groups Chosen independently;
R ⁷ is a linear, branched or cyclic C ₁ -C ₇ hydrocarbyl group or a C ₁ -C ₇ hydrocarbyloxy group;
"N" is zero or 1, when n is zero Thus, there is no carbon atoms and R ⁷ itself with R ^7, depicted ring, the carbon atom bearing R ³ C (O) HN group Directly bound;
R ¹⁰ is an unsubstituted linear, branched or cyclic C ₁ -C ₇ hydrocarbyl group, or a C ₁ -C ₇ hydrocarbyloxy group, or R ¹⁰ is an optionally substituted cyclic C ₅ -C ₇ hydrocarbyl group or optionally substituted C ₅ -C ₇ hydrocarbyloxy group, the optional substituents thereof being one or two groups R ⁸ and R ⁹ , identical or different, and straight chain, branched and cyclic C ₁ -C ₇ hydrocarbyl groups, and C ₁ -C ₇ selected hydrocarbyl independently from the group consisting of oxy group; and atoms having adjacent asterisk is chiral)
A compound equivalent to   The compound according to claim 1, wherein Z is CH which is part of a double bond.   The compound according to claim 2, wherein n is 1.   A compound according to claim 3, wherein the ring comprises two fused rings each containing 6 atoms.   The compound according to claim 1, wherein Z is oxygen.   6. The compound of claim 5, wherein n is zero.   7. The compound of claim 6, wherein the ring comprises one ring containing 5 ring atoms. The compound according to claim 1, wherein R ⁷ is a linear C ₁ -C ₃ hydrocarbyl group or a C ₁ -C ₃ hydrocarbyloxy group. The compound according to claim 1, wherein R ¹⁰ is phenyl, R ⁸ and R ⁹ are the same substituent, and a) 3 and 5 positions or b) 2 and 6 positions. And R ^7, and the phenyl ring containing the R ⁸ and R ⁹ substituent is in the relationship of syn or anti, A compound according to claim 9. n is 1, Z is CH, and the structure of the compound is represented by the following formula A1 or A2,
(Wherein ^* , R ³ , R ⁵ , R ⁶ , R ⁷ and R ¹⁰ are as defined above)
The compound according to claim 1, which corresponds to 12. A compound according to claim 11, wherein R ¹⁰ is phenyl, R ⁸ and R ⁹ are identical substituents and are attached at a) 3 and 5 positions or b) 2 and 6 positions. . And R ^7, and the phenyl ring containing the R ⁸ and R ⁹ substituent is in the relationship of syn or anti, compound of claim 12. 14. The compound of claim 13, wherein R ⁸ and R ⁹ are t-butyl.   15. The compound according to claim 14, wherein the structure of the compound corresponds to Formula A-1. One of R ⁵ and R ^6, but is hydrido, A compound according to claim 15. R ⁵ and R ⁶ are both hydrido compound according to claim 15. R ³ C (O) is acetyl The compound of claim 15. n is 1, Z is oxygen, the structure of the compound corresponds to the following formula A-3, or n is zero, Z is oxygen, the structure of the compound is The compound according to claim 1, which corresponds to the following formula A-4, and ^* , R ³ , R ⁵ , R ⁶ , R ⁷ and R ¹⁰ are as defined above.
One of R ⁵ and R ^6, but is hydrido, A compound according to claim 19.   20. The compound of claim 19, wherein the structure corresponds to Formula A-4. R ³ is C1 (methyl), or fluoro substituted benzoyl group, A compound according to claim 21. R ⁵ is a hydride, a compound of claim 21. R ⁶ is a benzyl group, the ring is substituted with 1-5 fluoro groups A compound according to claim 23. R ¹⁰ is a linear or branched C ₁ -C ₆ hydrocarbyl group A compound according to claim 21. Pd (II) catalyzed chiral insertion of aryl or heteroaryl substituents at the β-carbon of a protected prochiral carboxylic acid substrate to give an insertion product whose enantiomer ratio is greater than that of the other enantiomer Method, the following steps
a) (i) Formula I below
A protected carboxylic acid substrate molecule, (ii) an excess of aromatic or heteroaromatic iodide reactant relative to said substrate, (iii) a catalytic amount of Pd (II) catalyst, (iv) a protected of formula I Chiral acyl protecting ligand (L) of formula A present in an amount of about 5 to about 20 mole percent based on the amount of carboxylic acid substrate molecule, and (v) an excess of silver relative to said protected carboxylic acid substrate Heating the reaction mixture containing the solvent in which the compound oxidant is dispersed or dissolved in the sealed pressure vessel at a temperature of about 70 ° C to about 120 ° C;
b) performing the insertion to maintain the reaction mixture for a time and temperature sufficient to form an insertion product,
Including
In the compounds of formula I
i) R ^a is a hydride, a protected amino group (NPG), or a C ₁ -C ₆ hydrocarbyl linear or branched substituent, and one or two of R ^b and R ^c are hydrides; Otherwise, the R ^b and R ^c groups may be C ₁ -C ₁₃ hydrocarbyl linear or branched or cyclic aliphatic groups; or each may be nitrogen or may be two nitrogens and one oxygen (Methyl) C ₆ -C ₁₀ aromatic or heteroaromatic group containing up to 3 heteroatoms, the ring of this (methyl) C ₆ -C ₁₀ aromatic or heteroaromatic group being substituted Medicine or halogen other than iodine, C ₁ -C ₆ hydrocarbyl, C ₁ -C ₆ hydrocarbyloxy, carboxy C ₁ -C ₆ hydrocarbyl, trifluoromethyl, C ₁ -C ₆ hydrocarbyl Boyle, C ₁ -C ₆ hydrocarbyl carboxylate, nitro, C ₁ -C ₆ hydrocarbylthio oxy, cyano and protection Substituted with up to three selected from one or more of the group consisting of amino independently; and
(ii) X in the molecule of formula I is an NHR ² group, provided that R ² is a perfluorinated p-tolyl group [4- (CF ₃ ) C ₆ F ₄ ], OH, or -OC ₁ -C ₁₂ a hydrocarbyl group, X is _{therefore, NH [4- (CF 3)} C 6 F 4], is NOH or NH-OC ₁ -C ₁₂ hydrocarbyl group.), hydrocarbyl carboxylate, nitro, C ₁ -C ₆ Hydrocarbylthiooxy, cyano and protected amino; and said aromatic or heteroaromatic iodide reactant is unsubstituted or contains up to three substituents in addition to the iodo group, additional substituents are halogen other than iodine, C ₁ -C ₆ hydrocarbyl, C ₁ -C ₆ hydrocarbyloxy, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ hydrocarbyl Boyle, C ₁ -C ₆ hydrocarbyl carboxylate , hydrocarbylthio oxy, nitro, cyano, methylenedioxy, C ₂ -C ₆ vicinyl Oxyalkyl group, and C ₁ -C ₆ hydrocarbyl bilge -C ₁ -C ₆ are selected independently from one or more of the group consisting of alkyl phosphonates; and the protected ligand L according to claim 1 The process of being a compound of formula A of   27. The method of claim 26, wherein Z is CH which is part of a double bond.   28. The method of claim 27, wherein n is one.   29. The method of claim 28, wherein the ring comprises two fused rings each containing 6 atoms.   27. The method of claim 26, wherein Z is oxygen.   31. The method of claim 30, wherein n is zero.   32. The method of claim 31, wherein the ring comprises one ring containing 5 ring atoms. R ⁷ is a straight-chain C ₁ -C ₃ hydrocarbyl radical, or C ₁ -C ₃ hydrocarbyloxy group, The method of claim 26. 27. The method of claim 26, wherein R ¹⁰ is phenyl and R ⁸ and R ⁹ are the same substituent and are attached at a) 3 and 5 positions or b) 2 and 6 positions. . And R ^7, and the phenyl ring containing the R ⁸ and R ⁹ substituent is in the relationship of syn or anti, The method of claim 34.   27. A method according to claim 26, comprising the further step of recovering the reaction product.